95 results on '"Charbel Massaad"'
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2. RNA-Seq is not required to determine stable reference genes for qPCR normalization.
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Nirmal Kumar Sampathkumar, Venkat Krishnan Sundaram, Prakroothi S Danthi, Rasha Barakat, Shiden Solomon, Mrityunjoy Mondal, Ivo Carre, Tatiana El Jalkh, Aïda Padilla-Ferrer, Julien Grenier, Charbel Massaad, and Jacqueline C Mitchell
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Biology (General) ,QH301-705.5 - Abstract
Assessment of differential gene expression by qPCR is heavily influenced by the choice of reference genes. Although numerous statistical approaches have been proposed to determine the best reference genes, they can give rise to conflicting results depending on experimental conditions. Hence, recent studies propose the use of RNA-Seq to identify stable genes followed by the application of different statistical approaches to determine the best set of reference genes for qPCR data normalization. In this study, however, we demonstrate that the statistical approach to determine the best reference genes from commonly used conventional candidates is more important than the preselection of 'stable' candidates from RNA-Seq data. Using a qPCR data normalization workflow that we have previously established; we show that qPCR data normalization using conventional reference genes render the same results as stable reference genes selected from RNA-Seq data. We validated these observations in two distinct cross-sectional experimental conditions involving human iPSC derived microglial cells and mouse sciatic nerves. These results taken together show that given a robust statistical approach for reference gene selection, stable genes selected from RNA-Seq data do not offer any significant advantage over commonly used reference genes for normalizing qPCR assays.
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- 2022
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3. Retracing Schwann Cell Developmental Transitions in Embryonic Dissociated DRG/Schwann Cell Cocultures in Mice
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Venkat Krishnan Sundaram, Tatiana El Jalkh, Rasha Barakat, Camille Julie Isabelle Fernandez, Charbel Massaad, and Julien Grenier
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Schwann cell development ,dissociated DRG/SC cocultures ,Schwann cell precursors ,immature Schwann cells ,myelinating Schwann cells ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Embryonic Dissociated Dorsal Root Ganglia (DRG) cultures are often used to investigate the role of novel molecular pathways or drugs in Schwann cell development and myelination. These cultures largely recapitulate the order of cellular and molecular events that occur in Schwann cells of embryonic nerves. However, the timing of Schwann cell developmental transitions, notably the transition from Schwann Cell Precursors (SCP) to immature Schwann cells (iSC) and then to myelinating Schwann cells, has not been estimated so far in this culture system. In this study, we determined the expression profiles of Schwann cell developmental genes during the first week of culture and then compared our data to the expression profiles of these genes in developing spinal nerves. This helped in identifying that SCP transition into iSC between the 5th and 7th day in vitro. Furthermore, we also investigated the transition of immature cells into pro-myelinating and myelinating Schwann cells upon the induction of myelination in vitro. Our results suggest that Schwann cell differentiation beyond the immature stage can be observed as early as 4 days post the induction of myelination in cocultures. Finally, we compared the myelinating potential of coculture-derived Schwann cell monocultures to cultures established from neonatal sciatic nerves and found that both these culture systems exhibit similar myelinating phenotypes. In effect, our results allow for a better understanding and interpretation of coculture experiments especially in studies that aim to elucidate the role of a novel actor in Schwann cell development and myelination.
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- 2021
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4. Mutation of Proteolipid Protein 1 Gene: From Severe Hypomyelinating Leukodystrophy to Inherited Spastic Paraplegia
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Guy Khalaf, Claudia Mattern, Mélina Begou, Odile Boespflug-Tanguy, Charbel Massaad, and Liliane Massaad-Massade
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Pelizaeus-Merzbacher disease (PMD) ,spastic paraplegia (SPG2) ,diagnosis ,proteolipid protein 1 variants ,animal models ,treatments ,Biology (General) ,QH301-705.5 - Abstract
Pelizaeus–Merzbacher Disease (PMD) is an inherited leukodystrophy affecting the central nervous system (CNS)—a rare disorder that especially concerns males. Its estimated prevalence is 1.45–1.9 per 100,000 individuals in the general population. Patients affected by PMD exhibit a drastic reduction or absence of myelin sheaths in the white matter areas of the CNS. The Proteolipid Protein 1 (PLP1) gene encodes a transmembrane proteolipid protein. PLP1 is the major protein of myelin, and it plays a key role in the compaction, stabilization, and maintenance of myelin sheaths. Its function is predominant in oligodendrocyte development and axonal survival. Mutations in the PLP1 gene cause the development of a wide continuum spectrum of leukopathies from the most severe form of PMD for whom patients exhibit severe CNS hypomyelination to the relatively mild late-onset type 2 spastic paraplegia, leading to the concept of PLP1-related disorders. The genetic diversity and the biochemical complexity, along with other aspects of PMD, are discussed to reveal the obstacles that hinder the development of treatments. This review aims to provide a clinical and mechanistic overview of this spectrum of rare diseases.
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- 2022
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5. Targeting demyelination via α-secretases promoting sAPPα release to enhance remyelination in central nervous system
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Gemma Llufriu-Dabén, Alex Carrete, Elena Chierto, Jo Mailleux, Emeline Camand, Anne Simon, Tim Vanmierlo, Christiane Rose, Bernadette Allinquant, Jerome J.A. Hendriks, Charbel Massaad, Delphine Meffre, and Mehrnaz Jafarian-Tehrani
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Etazolate ,α-Secretase ,sAPPα ,Myelin ,Oligodendrocyte ,De/remyelination ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5weeks. To test the protective effect and the remyelination potential of etazolate, an α-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPPα in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr+ adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an α-secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPPα treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPPα release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPPα release in demyelinating disorders.
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- 2018
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6. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.
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Carles Vilariño-Güell, Alexander Zimprich, Filippo Martinelli-Boneschi, Bruno Herculano, Zhe Wang, Fuencisla Matesanz, Elena Urcelay, Koen Vandenbroeck, Laura Leyva, Denis Gris, Charbel Massaad, Jacqueline A Quandt, Anthony L Traboulsee, Mary Encarnacion, Cecily Q Bernales, Jordan Follett, Irene M Yee, Maria G Criscuoli, Angela Deutschländer, Eva M Reinthaler, Tobias Zrzavy, Elisabetta Mascia, Andrea Zauli, Federica Esposito, Antonio Alcina, Guillermo Izquierdo, Laura Espino-Paisán, Jorge Mena, Alfredo Antigüedad, Patricia Urbaneja-Romero, Jesús Ortega-Pinazo, Weihong Song, and A Dessa Sadovnick
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Genetics ,QH426-470 - Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.
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- 2019
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7. Optimal use of statistical methods to validate reference gene stability in longitudinal studies.
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Venkat Krishnan Sundaram, Nirmal Kumar Sampathkumar, Charbel Massaad, and Julien Grenier
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Medicine ,Science - Abstract
Multiple statistical approaches have been proposed to validate reference genes in qPCR assays. However, conflicting results from these statistical methods pose a major hurdle in the choice of the best reference genes. Recent studies have proposed the use of at least three different methods but there is no consensus on how to interpret conflicting results. Researchers resort to averaging the stability ranks assessed by different approaches or attributing a weighted rank to candidate genes. However, we report here that the suitability of these validation methods can be influenced by the experimental setting. Therefore, averaging the ranks can lead to suboptimal assessment of stable reference genes if the method used is not suitable for analysis. As the respective approaches of these statistical methods are different, a clear understanding of the fundamental assumptions and the parameters that influence the calculation of reference gene stability is necessary. In this study, the stability of 10 candidate reference genes (Actb, Gapdh, Tbp, Sdha, Pgk1, Ppia, Rpl13a, Hsp60, Mrpl10, Rps26) was assessed using four common statistical approaches (GeNorm, NormFinder, Coefficient of Variation or CV analysis and Pairwise ΔCt method) in a longitudinal experimental setting. We used the development of the cerebellum and the spinal cord of mice as a model to assess the suitability of these statistical methods for reference gene validation. GeNorm and the Pairwise ΔCt were found to be ill suited due to a fundamental assumption in their stability calculations. Highly correlated genes were given better stability ranks despite significant overall variation. NormFinder fares better but the presence of highly variable genes influences the ranking of all genes because of the algorithm's construct. CV analysis estimates overall variation, but it fails to consider variation across groups. We thus highlight the assumptions and potential pitfalls of each method using our longitudinal data. Based on our results, we have devised a workflow combining NormFinder, CV analysis along with visual representation of mRNA fold changes and one-way ANOVA for validating reference genes in longitudinal studies. This workflow proves to be more robust than any of these methods used individually.
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- 2019
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8. Specific Physical Exercise Improves Energetic Metabolism in the Skeletal Muscle of Amyotrophic-Lateral- Sclerosis Mice
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Céline Desseille, Séverine Deforges, Olivier Biondi, Léo Houdebine, Domenico D’amico, Antonin Lamazière, Cédric Caradeuc, Gildas Bertho, Gaëlle Bruneteau, Laure Weill, Jean Bastin, Fatima Djouadi, François Salachas, Philippe Lopes, Christophe Chanoine, Charbel Massaad, and Frédéric Charbonnier
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amyotrophic lateral sclerosis ,swimming ,running ,lipid ,glucose metabolism ,autophagy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Amyotrophic Lateral Sclerosis is an adult-onset neurodegenerative disease characterized by the specific loss of motor neurons, leading to muscle paralysis and death. Although the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS)-induced toxicity for motor neurons remain poorly understood, growing evidence suggest a defective energetic metabolism in skeletal muscles participating in ALS-induced motor neuron death ultimately destabilizing neuromuscular junctions. In the present study, we report that a specific exercise paradigm, based on a high intensity and amplitude swimming exercise, significantly improves glucose metabolism in ALS mice. Using physiological tests and a biophysics approach based on nuclear magnetic resonance (NMR), we unexpectedly found that SOD1(G93A) ALS mice suffered from severe glucose intolerance, which was counteracted by high intensity swimming but not moderate intensity running exercise. Furthermore, swimming exercise restored the highly ALS-sensitive tibialis muscle through an autophagy-linked mechanism involving the expression of key glucose transporters and metabolic enzymes, including GLUT4 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Importantly, GLUT4 and GAPDH expression defects were also found in muscles from ALS patients. Moreover, we report that swimming exercise induced a triglyceride accumulation in ALS tibialis, likely resulting from an increase in the expression levels of lipid transporters and biosynthesis enzymes, notably DGAT1 and related proteins. All these data provide the first molecular basis for the differential effects of specific exercise type and intensity in ALS, calling for the use of physical exercise as an appropriate intervention to alleviate symptoms in this debilitating disease.
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- 2017
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9. Liver X Receptors and Their Implications in the Physiology and Pathology of the Peripheral Nervous System
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Venkat Krishnan Sundaram, Charbel Massaad, and Julien Grenier
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LXR ,oxysterol ,cholesterol ,peripheral nervous system ,myelin ,schwann cell ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System.
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- 2019
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10. Wnt/β-catenin signaling pathway is a direct enhancer of thyroid transcription factor-1 in human papillary thyroid carcinoma cells.
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Marie Gilbert-Sirieix, Joelle Makoukji, Shioko Kimura, Monique Talbot, Bernard Caillou, Charbel Massaad, and Liliane Massaad-Massade
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Medicine ,Science - Abstract
The Wnt/β-catenin signaling pathway is involved in the normal development of thyroid gland, but its disregulation provokes the appearance of several types of cancers, including papillary thyroid carcinomas (PTC) which are the most common thyroid tumours. The follow-up of PTC patients is based on the monitoring of serum thyroglobulin levels which is regulated by the thyroid transcription factor 1 (TTF-1): a tissue-specific transcription factor essential for the differentiation of the thyroid. We investigated whether the Wnt/β-catenin pathway might regulate TTF-1 expression in a human PTC model and examined the molecular mechanisms underlying this regulation. Immunofluorescence analysis, real time RT-PCR and Western blot studies revealed that TTF-1 as well as the major Wnt pathway components are co-expressed in TPC-1 cells and human PTC tumours. Knocking-down the Wnt/β-catenin components by siRNAs inhibited both TTF-1 transcript and protein expression, while mimicking the activation of Wnt signaling by lithium chloride induced TTF-1 gene and protein expression. Functional promoter studies and ChIP analysis showed that the Wnt/β-catenin pathway exerts its effect by means of the binding of β-catenin to TCF/LEF transcription factors on the level of an active TCF/LEF response element at [-798, -792 bp] in TTF-1 promoter. In conclusion, we demonstrated that the Wnt/β-catenin pathway is a direct and forward driver of the TTF-1 expression. The localization of TCF-4 and TTF-1 in the same area of PTC tissues might be of clinical relevance, and justifies further examination of these factors in the papillary thyroid cancers follow-up.
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- 2011
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11. Cross-talk between oxysterols and glucocorticoids: differential regulation of secreted phopholipase A2 and impact on oligodendrocyte death.
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Amalia Trousson, Joelle Makoukji, Patrice X Petit, Sophie Bernard, Christian Slomianny, Michael Schumacher, and Charbel Massaad
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Medicine ,Science - Abstract
Oxysterols are oxidized forms of cholesterol. They have been shown to be implicated in cholesterol turnover, inflammation and in neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis. Glial cells are targets of oxysterols: they inhibit astrocyte proliferation after brain injury, and we have previously shown that 25-hydroxycholesterol (25OH) provokes oligodendrocyte apoptosis and stimulates the expression of sPLA2 type IIA (sPLA2-IIA), which has a protective effect.As glucocorticoids are well-known for their anti-inflammatory effects, our aim was to understand their direct effects on oxysterol-induced responses in oligodendrocytes (sPLA2-IIA stimulation and apoptosis). We demonstrate that the synthetic glucocorticoid dexamethasone (Dex) abolishes the stimulation of sPLA2-IIA by 25-hydroxycholesterol (25-OH). This inhibition is mediated by the glucocorticoid receptor (GR), which decreases the expression of the oxysterol receptor Pregnane X Receptor (PXR) and interferes with oxysterol signaling by recruiting a common limiting coactivator PGC1alpha. Consistent with the finding that sPLA2-IIA can partially protect oligodendrocytes against oxysterol-triggered apoptosis, we demonstrate here that the inhibition of sPLA2-IIA by Dex accelerates the apoptotic phenomenon, leading to a shift towards necrosis. We have shown by atomic force microscopy and electron microscopy that 25-OH and Dex alters oligodendrocyte shape and disorganizes the cytoplasm.Our results provide a new understanding of the cross-talk between oxysterol and glucocorticoid signaling pathways and their respective roles in apoptosis and oligodendrocyte functions.
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- 2009
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12. Mineralocorticoid Receptor knockout in Schwann cells alters myelin sheath thickness
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Alberto González Mayoral, Axel Eid, Razmig Derounian, Virginia Sofia Campanella, Andreia da Silva Ramos, Romy El Khoury, Charbel Massaad, and Damien Le Menuet
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Endocrinology ,Endocrinology, Diabetes and Metabolism - Abstract
Myelination allows fast and synchronized nerve influxes and is provided by Schwann cells in the peripheral nervous system. Glucocorticoid hormones are major regulators of stress, metabolism and immunity affecting all tissues. They act by binding to two receptors, the low affinity glucocorticoid receptor (GR) and the high affinity mineralocorticoid receptor (MR). Little is known on the effect of glucocorticoid hormones on the PNS and this study focuses on deciphering the role of MR in peripheral myelination. In this work, the presence of a functional MR in Schwann cells is demonstrated and the expression of MR protein in mouse sciatic nerve SC is evidenced. Besides, knockout of MR in SC (SCMRKO using Cre-lox system with DesertHedgeHog (Dhh) Cre promoter) was undertaken in mice. SCMRKO was not associated with alterations of performance in motor behavioral tests on 2- to 6-month old male mice compared to their controls. No obvious modifications of myelin gene expression or MR signaling gene expression were observed in the SCMRKO sciatic nerves. Nevertheless, Gr transcript and GR protein amounts were significantly increased in SCMRKO nerves compared to controls, suggesting a possible compensatory effect. Besides, an increase in myelin sheath thickness was noted for axons with perimeters larger than 15 µm in SCMRKO illustrated by a significant 4.5 % reduction in g-ratio (axon perimeter/myelin sheath perimeter). Thus, we defined MR as a new player in peripheral system myelination and in SC homeostasis.
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- 2023
13. Supplementary Table S2 from The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis
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Eric Pasmant, Charbel Massaad, Ivan Bièche, Béatrice Parfait, Pierre Wolkenstein, Dominique Vidaud, Michel Vidaud, Laurent Lantieri, Benoît Terris, Frédérique Larousserie, Laurence Valeyrie-Allanore, Thomas De Raedt, Didier Borderie, Mikael Hivelin, Valérie Dumaine, Karen Leroy, François Lallemand, Jennifer Varin, Nicolas Ortonne, Ingrid Laurendeau, Julien Masliah-Planchon, Ghjuvan'Ghjacumu Shackleford, and Armelle Luscan
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PDF file 97K, List of the 89 Wnt pathway selected genes
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- 2023
14. Supplementary Figure S1 from The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis
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Eric Pasmant, Charbel Massaad, Ivan Bièche, Béatrice Parfait, Pierre Wolkenstein, Dominique Vidaud, Michel Vidaud, Laurent Lantieri, Benoît Terris, Frédérique Larousserie, Laurence Valeyrie-Allanore, Thomas De Raedt, Didier Borderie, Mikael Hivelin, Valérie Dumaine, Karen Leroy, François Lallemand, Jennifer Varin, Nicolas Ortonne, Ingrid Laurendeau, Julien Masliah-Planchon, Ghjuvan'Ghjacumu Shackleford, and Armelle Luscan
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PDF file 161K, A simplified representation of the three different Wnt signalling pathways: the canonical pathway, the planar cell polarity pathway, and the Wnt/calcium pathway. In the absence of Wnt ligand, the 'destruction complex' composed of the core proteins Axin, adenomatous polyposis coli (APC), and glycogen synthase kinase-3 (GSK3) rapidly phosphorylates cytosolic beta-catenin, targeting it for subsequent proteasome-mediated destruction. Binding of Wnt to Frizzled (FZD) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates the cytosolic protein Dishevelled (DVL), leading to inhibition of the destruction complex. The resulting accumulated beta-catenin can then translocate to the nucleus to activate Wnt-responsive target genes regulated by lymphoid enhancer factor (LEF) and T cell factor (TCF) family transcription factors, leading to various cellular effects. The secreted inhibitor Dickkopf (DKK) can antagonize Wnt signalling by competitively binding to LRP5/6. Secreted FZD-related proteins (SFRPs) and Wnt inhibitory factor (WIF) are thought to antagonize Wnt signalling by sequestering Wnt ligand in the extracellular space. Binding of Wnt isoforms to FZD can trigger beta-catenin-independent downstream signalling events, other so-called non-canonical Wnt pathways that do not require the transcriptional activity of beta-catenin. One branch of non-canonical pathways involves the activation of RHO and RAC small G proteins to regulate the actin cytoskeleton. DVL-associated activator of morphogenesis 1 (DAAM1), when complexed with DVL and RHO, acts through the regulation of RHO-associated protein kinases (ROCK) and the DVL-RAC GTPase complex to affect actin remodelling. Another branch, when activated, is defined by a phospholipase C (PLC)-mediated increase in intracellular Ca2+ levels and Ca2+ fluxes that lead to the activation of Ca2+/calmodulin-dependent protein kinase (CaMK), protein kinase C (PKC), and nuclear factor of activated T cells (NFAT)
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- 2023
15. Data from The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis
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Eric Pasmant, Charbel Massaad, Ivan Bièche, Béatrice Parfait, Pierre Wolkenstein, Dominique Vidaud, Michel Vidaud, Laurent Lantieri, Benoît Terris, Frédérique Larousserie, Laurence Valeyrie-Allanore, Thomas De Raedt, Didier Borderie, Mikael Hivelin, Valérie Dumaine, Karen Leroy, François Lallemand, Jennifer Varin, Nicolas Ortonne, Ingrid Laurendeau, Julien Masliah-Planchon, Ghjuvan'Ghjacumu Shackleford, and Armelle Luscan
- Abstract
Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies.Experimental Design: The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial–mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines.Results: The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active β-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann–mesenchymal transition.Conclusion: We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis. Clin Cancer Res; 20(2); 358–71. ©2013 AACR.
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- 2023
16. Data from Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-α Expression in Breast Cancer Cells
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Liliane Massaad-Massade, Robert Barouki, Charbel Massaad, Vincent Favaudon, Nathalie Mazure, Thérèse Hervèe Mayi, Fabrice Lecuru, Marie-Aude Le Frère Belda, Marie-Claude Fulchignoni-Lataud, Etienne Blanc, Anne Dreiem, and Ramzi Seifeddine
- Abstract
The transcription factor CCAAT/enhancer binding protein-α (C/EBPα) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBPα mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-β-d-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBPα mRNA by ∼30%. C/EBPα gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (−522; −527 bp), which binds to hypoxia-inducible factor (HIF)-1α, as essential for down-regulation of C/EBPα transcription in hypoxia. Immunocytochemical analysis showed that C/EBPα was localized in the nucleus at 21% O2, but was mostly cytoplasmic under 1% O2. Knockdown of HIF-1α by RNAi restored C/EBPα to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBPα and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBPα expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBPα in hypoxia is mediated by HIF-1. [Cancer Res 2008;68(7):2158–65]
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- 2023
17. Supplementary Figures 1-4 from Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-α Expression in Breast Cancer Cells
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Liliane Massaad-Massade, Robert Barouki, Charbel Massaad, Vincent Favaudon, Nathalie Mazure, Thérèse Hervèe Mayi, Fabrice Lecuru, Marie-Aude Le Frère Belda, Marie-Claude Fulchignoni-Lataud, Etienne Blanc, Anne Dreiem, and Ramzi Seifeddine
- Abstract
Supplementary Figures 1-4 from Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-α Expression in Breast Cancer Cells
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- 2023
18. Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway
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Domenico D'Amico, Olivier Biondi, Camille Januel, Cynthia Bezier, Delphine Sapaly, Zoé Clerc, Mirella El Khoury, Venkat Krishnan Sundaram, Léo Houdebine, Thibaut Josse, Bruno Della Gaspera, Cécile Martinat, Charbel Massaad, Laure Weill, and Frédéric Charbonnier
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Motor Neurons ,X-Box Binding Protein 1 ,Histology ,Protein Serine-Threonine Kinases ,Survival of Motor Neuron 1 Protein ,Pathology and Forensic Medicine ,Activating Transcription Factor 6 ,Cell Line ,Muscular Atrophy, Spinal ,Disease Models, Animal ,Mice ,Neurology ,Physiology (medical) ,Endoribonucleases ,Animals ,Humans ,Neurology (clinical) - Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by survival of motor neuron (SMN) deficiency that induces motor neuron (MN) degeneration and severe muscular atrophy. Gene therapies that increase SMN have proven their efficacy but not for all patients. Here, we explored the unfolded protein response (UPR) status in SMA pathology and explored whether UPR modulation could be beneficial for SMA patients.We analysed the expression and activation of key UPR proteins by RT-qPCR and by western blots in SMA patient iPSC-derived MNs and one SMA cell line in which SMN expression was re-established (rescue). We complemented this approach by using myoblast and fibroblast SMA patient cells and SMA mouse models of varying severities. Finally, we tested in vitro and in vivo the effect of IRE1α/XBP1 pathway restoration on SMN expression and subsequent neuroprotection.We report that the IRE1α/XBP1 branch of the unfolded protein response is disrupted in SMA, with a depletion of XBP1s irrespective of IRE1α activation pattern. The overexpression of XBP1s in SMA fibroblasts proved to transcriptionally enhance SMN expression. Importantly, rebalancing XBP1s expression in severe SMA-like mice, induced SMN expression and spinal MN protection.We have identified XBP1s depletion as a contributing factor in SMA pathogenesis, and the modulation of this transcription factor proves to be a plausible therapeutic avenue in the context of pharmacological interventions for patients.
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- 2022
19. Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice
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Stephanie Eid, Sami T. Azar, Mary E Haddad, Christian Boitard, Julien Grenier, Philippe Wiesel, Mohamed El Massry, Assaad A. Eid, Charbel Massaad, Batoul Dia, Selim Aractingi, Rasha Barakat, Mehdi Hichor, Cédric Szyndralewiez, Ghazi Zaatari, Johan Chanal, and Suzan S. Boutary
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Male ,0301 basic medicine ,Hydrocarbons, Fluorinated ,Pyridines ,Pyridones ,Endocrinology, Diabetes and Metabolism ,Schwann cell ,030209 endocrinology & metabolism ,Diabetes Mellitus, Experimental ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Diabetic Neuropathies ,Internal Medicine ,medicine ,Animals ,Humans ,Pyrazolones ,Liver X receptor ,Aged ,Liver X Receptors ,Aged, 80 and over ,Sulfonamides ,NADPH oxidase ,biology ,business.industry ,NOX4 ,medicine.disease ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,Peripheral neuropathy ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,NADPH Oxidase 4 ,biology.protein ,Cancer research ,Pyrazoles ,Female ,Schwann Cells ,Signal transduction ,Reactive Oxygen Species ,business ,Myelin Proteins ,Homeostasis ,Signal Transduction - Abstract
Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)–producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.
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- 2020
20. Author Reply to Peer Reviews of RNA-Seq is not required to determine stable reference genes for qPCR normalization
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Jacqueline C Mitchell, Charbel Massaad, Julien Grenier, Aïda Padilla-Ferrer, Tatiana El Jalkh, Ivo Carre, Mrityunjoy Mondal, Shiden Solomon, Rasha Barakat, Prakroothi S Danthi, Venkat Krishnan Sundaram, and Nirmal Kumar Sampathkumar
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- 2021
21. RNA-Seq is not required to determine stable reference genes for qPCR normalization
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Jacqueline C. Mitchell, Shiden Solomon, Tatiana El Jalkh, Mrityunjoy Mondal, Nirmal Kumar Sampathkumar, Charbel Massaad, Aïda Padilla-Ferrer, Julien Grenier, Rasha Barakat, Venkat Krishnan Sundaram, Prakroothi S Danthi, and Ivo Carre
- Subjects
Database normalization ,Normalization (statistics) ,Reference genes ,Gene expression ,Reference gene ,RNA-Seq ,Computational biology ,Biology ,Gene ,Selection (genetic algorithm) - Abstract
Assessment of differential gene expression by qPCR is heavily influenced by the choice of reference genes. Although numerous statistical approaches have been proposed to determine the best reference genes, they can give rise to conflicting results depending on experimental conditions. Hence, recent studies propose the use of RNA-Seq to identify stable genes followed by the application of different statistical approaches to determine the best set of reference genes for qPCR data normalization. In this study, we demonstrate that the statistical approach to determine the best reference genes from randomly selected candidates is more important than the preselection of stable candidates from RNA-Seq data. Using a qPCR data normalization workflow that we have previously established; we show that qPCR data normalization using randomly chosen conventional reference genes renders the same results as stable reference genes selected from RNA-Seq data. Furthermore, the differential expression of target genes assessed by qPCR using our normalization strategy is comparable to RNA-Seq results. We validated these observations in two distinct cross-sectional experimental conditions involving human iPSC derived microglial cells and mouse sciatic nerves. These results taken together show that given a robust statistical approach for reference gene selection, stable genes selected from RNA-Seq data do not offer any significant advantage over commonly used reference genes for normalizing qPCR assays.
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- 2021
22. Early Variations in White Matter Microstructure and Depression Outcome in Adolescents With Subthreshold Depression
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Sylvane Desrivières, Arun L.W. Bokde, Jean-Luc Martinot, Jani Penttilä, Betteke van Noort, Dimitri Papadopoulos-Orfanos, Luise Poustka, Hélène Vulser, Viola Kappel, Tomáš Paus, Gareth J. Barker, Yvonne Grimmer, Robert Goodman, Gunter Schumann, Marie-Laure Paillère Martinot, Robert Whelan, Uli Bromberg, Michael N. Smolka, Vincent Frouin, Charbel Massaad, Tahmine Fadai, Penny A. Gowland, Frauke Nees, Ruben Miranda, Juergen Gallinat, Argyris Stringaris, Christian Büchel, Henrik Walter, Andreas Heinz, Herve Lemaitre, Herta Flor, Eleni T. Tzavara, Anna Cattrell, Sarah Rodehacke, Eric Artiges, Patricia J. Conrod, Maren Struve, Tobias Banaschewski, Hugh Garavan, and Rüdiger Brühl
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Male ,medicine.medical_specialty ,Adolescent ,Prodromal Symptoms ,Uncinate fasciculus ,Neuroimaging ,Audiology ,Corpus callosum ,Corpus Callosum ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Surveys and Questionnaires ,Fractional anisotropy ,medicine ,Humans ,Cingulum (brain) ,Longitudinal Studies ,Anterior cingulate cortex ,Psychiatric Status Rating Scales ,Depression ,business.industry ,Brain ,White Matter ,030227 psychiatry ,Psychiatry and Mental health ,Diffusion Magnetic Resonance Imaging ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Case-Control Studies ,Female ,business ,030217 neurology & neurosurgery ,Diffusion MRI ,Tractography - Abstract
Objective: White matter microstructure alterations have recently been associated with depressive episodes during adolescence, but it is unknown whether they predate depression. The authors investigated whether subthreshold depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome. Method: Adolescents with subthreshold depression (N=96) and healthy control subjects (N=336) drawn from a community-based cohort were compared using diffusion tensor imaging and whole brain tract-based spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followed up at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines spreading from the regions identified in the TBSS analysis and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. The authors searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold depression and depression at follow-up, and then explored the specificity of the findings. Results: Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between subthreshold depression at baseline and depression at follow-up was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression. Conclusions: Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex may denote a higher risk of transition to depression in adolescents.
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- 2018
23. Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A
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Jean-Michel Vallat, Didier Desmaële, Laurence Richard, Céline Gracia, Julien Loisel-Duwattez, Marie Caillaud, Mévidette El Madani, David Adams, Alice Rouyer, Liliane Massaad-Massade, Patrick Couvreur, Michael Schumacher, Giorgia Urbinati, Andoni Echaniz-Laguna, Suzan Boutary, Charbel Massaad, Institut Galien Paris-Saclay (IGPS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Maladies et hormones du système nerveux (DHNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Neurologie [CHU Limoges], CHU Limoges, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire Interdisciplinaire Solidarités, Sociétés, Territoires (LISST), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-École Nationale Supérieure de Formation de l'Enseignement Agricole de Toulouse-Auzeville (ENSFEA)-Centre National de la Recherche Scientifique (CNRS), Maintenance Myélinique et Neuropathies Périphériques (MMNP), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Desmaële, Didier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,Time Factors ,Medicine (miscellaneous) ,Nanoconjugates ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Nerve Fibers, Myelinated ,Myelin ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Neurofilament Proteins ,RNA interference ,Medicine ,RNA, Small Interfering ,Biology (General) ,SOXE Transcription Factors ,Neurodegenerative diseases ,Gene Transfer Techniques ,3. Good health ,medicine.anatomical_structure ,RNA Interference ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Sciatic nerve ,General Agricultural and Biological Sciences ,Myelin Proteins ,Squalene ,congenital, hereditary, and neonatal diseases and abnormalities ,Neurofilament ,QH301-705.5 ,[CHIM.THER] Chemical Sciences/Medicinal Chemistry ,Transgene ,SOX10 ,Mice, Transgenic ,Motor Activity ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Animals ,Early Growth Response Protein 2 ,business.industry ,Regeneration (biology) ,Recovery of Function ,Nerve Regeneration ,Mice, Inbred C57BL ,Disease Models, Animal ,RNAi Therapeutics ,030104 developmental biology ,nervous system ,Preclinical research ,Cell culture ,business ,030217 neurology & neurosurgery - Abstract
Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment. We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in normalization of Pmp22 protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction, one major step in restoring function of myelin sheaths. The normalization of sciatic nerve Krox20, Sox10 and neurofilament levels reflected the regeneration of both myelin and axons. Importantly, the positive effects of siRNA PMP22-SQ NPs lasted for three weeks, and their renewed administration resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for inherited peripheral neuropathies. They provide the proof of concept for a new precision medicine based on the normalization of disease gene expression by siRNA., Boutary et al. describe siRNA based therapy conjugated with squalene nanoparticles as an efficient approach to normalize PMP22 protein levels, restore locomotor activity, electrophysiological parameters and function of myelin sheath in CMT1A mouse models. These findings could be useful to develop therapeutic strategies for inherited peripheral neuropathies.
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- 2021
24. Tissue damage from neutrophil-induced oxidative stress in COVID-19
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Philippe Nuss, Carole Elbim, Chrystel Becker, Mireille Laforge, Corinne Frere, Charbel Massaad, Jean-Jacques Benoliel, Miryana Hémadi, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS (UMR_7086)), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de psychiatrie adulte [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Laforge, Mireille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Psychiatrie adultes [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP]
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0301 basic medicine ,History ,Neutrophils ,[SDV]Life Sciences [q-bio] ,medicine.disease_cause ,Extracellular Traps ,Severity of Illness Index ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Antioxidants ,Acetylcysteine ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Lymphocytes ,Lung ,ComputingMilieux_MISCELLANEOUS ,chemistry.chemical_classification ,[SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,Sulfonamides ,[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,biology ,NF-kappa B ,Thrombosis ,3. Good health ,Computer Science Applications ,medicine.anatomical_structure ,Fuel Technology ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology ,Host-Pathogen Interactions ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Cytokines ,Drug Therapy, Combination ,Coronavirus Infections ,medicine.drug ,NF-E2-Related Factor 2 ,Pneumonia, Viral ,Glycine ,Proteinase Inhibitory Proteins, Secretory ,Energy Engineering and Power Technology ,Education ,Superoxide dismutase ,03 medical and health sciences ,Betacoronavirus ,medicine ,Humans ,Neutrophil to lymphocyte ratio ,Author Correction ,Pandemics ,[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity ,Reactive oxygen species ,business.industry ,SARS-CoV-2 ,Superoxide Dismutase ,COVID-19 ,NFKB1 ,medicine.disease ,Immunity, Innate ,Red blood cell ,Oxidative Stress ,030104 developmental biology ,chemistry ,Gene Expression Regulation ,Immunology ,biology.protein ,business ,Reactive Oxygen Species ,Oxidative stress ,030215 immunology - Abstract
The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS), which promote a cascade of biological events that drive pathological host responses. ROS induce tissue damage, thrombosis and red blood cell dysfunction, which contribute to COVID-19 disease severity. We suggest that free radical scavengers could be beneficial for the most vulnerable patients. In this Comment article, Becker and colleagues consider how the excessive release of reactive oxygen species by neutrophils may perpetuate red blood cell dysfunction, thrombosis and tissue damage in severe cases of COVID-19.
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- 2020
- Full Text
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25. Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: the past, the present and the future
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Julien Loisel-Duwattez, David H. Adams, Liliane Massaad-Massade, Andoni Echaniz-Laguna, Suzan Boutary, Michael Schumacher, Charbel Massaad, and INSERM U1195
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Small interfering RNA ,[SDV]Life Sciences [q-bio] ,Disease ,Bioinformatics ,03 medical and health sciences ,Tooth disease ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Physiology (medical) ,Peripheral myelin protein 22 ,Gene Duplication ,Gene duplication ,Medicine ,Humans ,Inherited neuropathy ,Pmp22 gene ,business.industry ,Biochemistry (medical) ,Public Health, Environmental and Occupational Health ,Chromosome ,General Medicine ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,business ,Myelin Proteins - Abstract
International audience; Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000. CMT1A represents 60%-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22). PMP22 gene is under tight regulation and small changes in its expression influences myelination and affect motor and sensory functions. To date, CMT1A treatment is symptomatic and classic pharmacological options have been disappointing. Here, we review the past, present, and future treatment options for CMT1A, with a special emphasis on the highly promising potential of PMP22-targeted small interfering RNA and antisense oligonucleotides.
- Published
- 2020
26. Author Correction: Tissue damage from neutrophil-induced oxidative stress in COVID-19
- Author
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Charbel Massaad, Mireille Laforge, Miryana Hémadi, Jean Jacques Benoliel, Corinne Frere, Carole Elbim, Philippe Nuss, Chrystel Becker, Gestionnaire, Hal Sorbonne Université, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Interfaces, Traitements, Organisation et Dynamique des Systèmes (ITODYS (UMR_7086)), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Psychiatrie adultes [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de psychiatrie adulte [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP]
- Subjects
0303 health sciences ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,030306 microbiology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,[SDV]Life Sciences [q-bio] ,Comment ,Energy Engineering and Power Technology ,Predictive markers ,medicine.disease_cause ,[SDV] Life Sciences [q-bio] ,03 medical and health sciences ,Fuel Technology ,Viral infection ,Immunology ,Tissue damage ,Medicine ,business ,Oxidative stress ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology - Abstract
The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS), which promote a cascade of biological events that drive pathological host responses. ROS induce tissue damage, thrombosis and red blood cell dysfunction, which contribute to COVID-19 disease severity. We suggest that free radical scavengers could be beneficial for the most vulnerable patients., In this Comment article, Becker and colleagues consider how the excessive release of reactive oxygen species by neutrophils may perpetuate red blood cell dysfunction, thrombosis and tissue damage in severe cases of COVID-19.
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- 2020
27. Liver X Receptor exerts a protective effect against the oxidative stress in the peripheral nerve
- Author
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Julien Grenier, Assaad A. Eid, Jean Bastin, Venkat Krishnan Sundaram, Ronza Abdel-Rassoul, Marin Manuel, Patrice X. Petit, Didier Borderie, Stephanie Eid, Charbel Massaad, Mehdi Hichor, Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Régulation de la transcription et maladies génétiques (RTMG), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,Male ,Mice, 129 Strain ,Hydrocarbons, Fluorinated ,NF-E2-Related Factor 2 ,Protein Carbonylation ,Schwann cell ,lcsh:Medicine ,medicine.disease_cause ,Article ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,tert-Butylhydroperoxide ,medicine ,Animals ,Homeostasis ,Liver X receptor ,lcsh:Science ,Myelin Sheath ,Liver X Receptors ,chemistry.chemical_classification ,Mice, Knockout ,Reactive oxygen species ,Sulfonamides ,Multidisciplinary ,Chemistry ,Superoxide ,[SCCO.NEUR]Cognitive science/Neuroscience ,lcsh:R ,Lipid metabolism ,Lipid Metabolism ,Sciatic Nerve ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Q ,Schwann Cells ,Reactive Oxygen Species ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
International audience; Reactive oxygen species (ROS) modify proteins and lipids leading to deleterious outcomes. Thus, maintaining their homeostatic levels is vital. This study highlights the endogenous role of LXRs (LXRα and β) in the regulation of oxidative stress in peripheral nerves. We report that the genetic ablation of both LXR isoforms in mice (LXRdKO) provokes significant locomotor defects correlated with enhanced anion superoxide production, lipid oxidization and protein carbonylation in the sciatic nerves despite the activation of Nrf2-dependant antioxidant response. Interestingly, the reactive oxygen species scavenger N-acetylcysteine counteracts behavioral, electrophysical, ultrastructural and biochemical alterations in LXRdKO mice. Furthermore, Schwann cells in culture pretreated with LXR agonist, TO901317, exhibit improved defenses against oxidative stress generated by tert-butyl hydroperoxide, implying that LXRs play an important role in maintaining the redox homeostasis in the peripheral nervous system. Thus, LXR activation could be a promising strategy to protect from alteration of peripheral myelin resulting from a disturbance of redox homeostasis in Schwann cell. Liver X Receptors (LXRα and LXRβ) belong to the nuclear receptor superfamily of ligand-activated transcription factors. They regulate target gene expression by binding to specific responsive elements and are implicated in metabolic processes such as cholesterol turnover, inflammation as well as pathologies such as cancer and neu-rodegenerative diseases 1. Natural ligands of LXRs are oxysterols (i.e. 24(S)-hydroxycholesterol (24(S)-OH) or 25-hydroxycholesterol (25-OH)), produced either through auto-oxidation or enzymatic oxidation of cholesterol. Synthetic ligands of LXR, like TO901317, have also been discovered and are known to be potent activators of the LXR pathway. Previous studies have shown that mice where both LXR isoforms (LXRα and LXRβ) are deleted (LXR double KO or LXRdKO) exhibit altered lipid homeostasis in the brain resulting in neuronal loss, astrocytic proliferation , disorganized myelin sheaths and lipid accumulation in specific brain regions that participates in locomo-tor defects highlighted in these animals 2,3. We also observed that LXRdKO mice have thinner myelin sheaths surrounding axons of the sciatic nerve 4,5. Importantly, LXR inhibition enhanced myelin gene transcripts but decreased the amount of myelin proteins, suggesting post-translational modifications, detrimental for peripheral myelin integrity. Oxidative stress has been recently shown to alter the structure of myelin proteins in several diabetic peripheral neuropathies 6. In particular, PMP22 misfolding and aggregation provokes demyelination and nerve conduction velocity reduction. In line with this, our team recently showed that a burst of oxidative stress induced by Paraquat provokes a dramatic alteration of myelin structure in the sciatic nerves 7. Indeed, because of their high reactivity, reactive oxygen species (ROS) modify the structure and therefore the physiological functions of proteins and lipids. Thus, maintaining normal cellular ROS levels is essential. The excessive production of ROS or the decrease of antioxidant defenses is rather a hallmark characteristic in the pathogenesis of diseases such as diabetes, athero-sclerosis and neurodegeneration 8,9. Hence, compounds that exhibit anti-oxidative effects, triggering the intracel-lular cascade of protective pathways, may offer a promising strategy for therapeutic applications 10 .
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- 2018
28. Targeting demyelination via α-secretases promoting sAPPα release to enhance remyelination in central nervous system
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Mehrnaz Jafarian-Tehrani, Anne Simon, Gemma Llufriu-Dabén, Christiane Rose, Jo Mailleux, Delphine Meffre, Emeline Camand, Bernadette Allinquant, Alex Carrete, Elena Chierto, Jerome J. A. Hendriks, Charbel Massaad, and Tim Vanmierlo
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Male ,0301 basic medicine ,Central nervous system ,Etazolate ,etazolate ,α-Secretase ,sAPPα ,myelin ,oligodendrocyte ,de/remyelination ,white matter ,lcsh:RC321-571 ,Corpus Callosum ,Amyloid beta-Protein Precursor ,Cuprizone ,03 medical and health sciences ,Myelin ,α secretase ,0302 clinical medicine ,Cerebellum ,De/remyelination ,medicine ,Animals ,Remyelination ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cells, Cultured ,Myelin Sheath ,biology ,White matter ,Brain ,Lysophosphatidylcholines ,De/remyelination, Etazolate, Myelin, Oligodendrocyte, White matter, sAPPα, α-Secretase ,Oligodendrocyte ,Axons ,Mice, Inbred C57BL ,Neuroprotective Agents ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,biology.protein ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,Neuroscience ,030217 neurology & neurosurgery ,Demyelinating Diseases - Abstract
Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5 weeks. To test the protective effect and the remyelination potential of etazolate, an α-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPPα in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr+ adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an α-secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPPα treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPPα release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPPα release in demyelinating disorders. We acknowledge the non-profit organizations “Fondation des Gueules Cassées” (grants 47-2015, 47-2016 to MJT; PhD fellowship 55-2014 to GLD; PhD fellowship 48-2015, 48-2016 to AC), “Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques” (grant AO2015-meffre to DM), Paris Descartes University and INSERM (Institut National de la Santé Et de la Recherche Médicale) for financially supporting this work.
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- 2018
29. mTORC2 Signaling Regulates Nox4-Induced Podocyte Depletion in Diabetes
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Yves Gorin, Stephanie Eid, Kawthar Braych, Sarah Moodad, Assaad A. Eid, Karen Block, Hanna E. Abboud, Charbel Massaad, Awad Rashid, Ramzi Sabra, Suzan S. Boutary, and Ahmed Hamdy
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Male ,0301 basic medicine ,medicine.medical_specialty ,Cell Survival ,Physiology ,Clinical Biochemistry ,Apoptosis ,Mechanistic Target of Rapamycin Complex 2 ,mTORC1 ,Biochemistry ,mTORC2 ,Diabetes Mellitus, Experimental ,Podocyte ,Mice ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,General Environmental Science ,biology ,urogenital system ,Podocytes ,TOR Serine-Threonine Kinases ,Forum Original Research CommunicationKidney – Part II of II (Y. Gorin, Ed.) ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,NADPH Oxidases ,NOX4 ,Cell Biology ,Diabetes Mellitus, Type 1 ,Glucose ,Rapamycin-Insensitive Companion of mTOR Protein ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,NADPH Oxidase 4 ,Multiprotein Complexes ,NOX1 ,Slit diaphragm ,Podocin ,biology.protein ,General Earth and Planetary Sciences ,Carrier Proteins ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Aim: Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. We explored the hypothesis that mammalian target of rapamycin complex 2 (mTORC2) mediates podocyte injury in diabetes. Results: High glucose (HG)-induced podocyte injury reflected by alterations in the slit diaphragm protein podocin and podocyte depletion/apoptosis. This was paralleled by activation of the Rictor/mTORC2/Akt pathway. HG also increased the levels of Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using small interfering RNA (siRNA)-targeting Rictor in vitro decreased HG-induced Nox1 and Nox4, NADPH oxidase activity, restored podocin levels, and reduced podocyte depletion/apoptosis. Inhibition of mTORC2 had no effect on mammalian target of rapamycin complex 1 (mTORC1) activation, described by our group to be increased in diabetes, suggesting that the mTORC2 activation by HG could mediate podocyte injury independently of mTORC1. In isolated glomeruli of OVE26 mice, there was a similar activation of the Rictor/mTORC2/Akt signaling pathway with increase in Nox4 and NADPH oxidase activity. Inhibition of mTORC2 using antisense oligonucleotides targeting Rictor restored podocin levels, reduced podocyte depletion/apoptosis, and attenuated glomerular injury and albuminuria. Innovation: Our data provide evidence for a novel function of mTORC2 in NADPH oxidase-derived reactive oxygen species generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes. Conclusion: mTORC2 and/or NADPH oxidase inhibition may represent a therapeutic modality for diabetic kidney disease. Antioxid. Redox Signal. 25, 703–719.
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- 2016
30. Liver X Receptors and Their Implications in the Physiology and Pathology of the Peripheral Nervous System
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Julien Grenier, Charbel Massaad, and Venkat Krishnan Sundaram
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Schwann cell ,Physiology ,Sensory system ,Stimulation ,Review ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,Myelin ,Ganglia, Sensory ,peripheral nervous system ,Humans ,Medicine ,Obesity ,Physical and Theoretical Chemistry ,Liver X receptor ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Liver X Receptors ,business.industry ,Organic Chemistry ,cholesterol ,Oxysterols ,General Medicine ,medicine.disease ,Computer Science Applications ,myelin ,Peripheral neuropathy ,medicine.anatomical_structure ,Allodynia ,lcsh:Biology (General) ,lcsh:QD1-999 ,Hyperalgesia ,Peripheral nervous system ,schwann cell ,LXR ,Schwann Cells ,medicine.symptom ,business ,oxysterol - Abstract
Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System.
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- 2019
31. Corrigendum to 'Differential regulation of Wnt/beta-catenin signaling by Liver X Receptors in Schwann cells and oligodendrocytes' [Biochem. Pharmacol. 86 (2013) 106–114]
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Delphine Meffre, Charbel Massaad, Philippe Liere, Julien Grenier, Joelle Makoukji, and Ghjuvan’Ghjacumu Shackleford
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Pharmacology ,Chemistry ,Differential regulation ,Wnt beta catenin signaling ,Liver X receptor ,Biochemistry ,Cell biology - Published
- 2020
32. Mechanical Stretch of High Magnitude Provokes Axonal Injury, Elongation of Paranodal Junctions, and Signaling Alterations in Oligodendrocytes
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Didier Borderie, Mehrnaz Jafarian-Tehrani, Elena Chierto, Giulia Cristinziano, Delphine Meffre, Francesca Castoldi, François Etienne, Anne Simon, François Rannou, Barclay Morrison, Francesca Sapone, Charbel Massaad, and Alex Carrete
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0301 basic medicine ,Cerebellum ,Strain (injury) ,Cell morphology ,Protein oxidation ,Mechanostimulation ,Antioxidants ,Myelin ,0302 clinical medicine ,Traumatic brain injury ,Stretch-induced injury ,Tensile strain ,Chemistry ,Oligodendrocytes ,Myelin Damage ,Glutathione ,Cell biology ,Oligodendroglia ,medicine.anatomical_structure ,Neurology ,Signal transduction ,Demyelination ,Oxidation-Reduction ,Myelin Proteins ,Signal Transduction ,MAP Kinase Signaling System ,Neuroscience (miscellaneous) ,Traumatic Brain Injury, Oxidative Stress, In-Vitro, Endothelial Cells, Myelin Damage, Protein Activation, Demyelination, Model, Remyelination ,Article ,Cell Line ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Tensile Strength ,medicine ,Cell Adhesion ,Animals ,Protein Activation ,Cell Shape ,White matter injury ,Endothelial Cells ,medicine.disease ,Oligodendrocyte ,Axons ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Remyelination ,Gene Expression Regulation ,Cell culture ,In-Vitro ,Stress, Mechanical ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Model - Abstract
Increasing findings suggest that demyelination may play an important role in the pathophysiology of brain injury, but the exact mechanisms underlying such damage are not well known. Mechanical tensile strain of brain tissue occurs during traumatic brain injury. Several studies have investigated the cellular and molecular events following a static tensile strain of physiological magnitude on individual cells such as oligodendrocytes. However, the pathobiological impact of high-magnitude mechanical strain on oligodendrocytes and myelinated fibers remains under investigated. In this study, we reported that an applied mechanical tensile strain of 30% on mouse organotypic culture of cerebellar slices induced axonal injury and elongation of paranodal junctions, two hallmarks of brain trauma. It was also able to activate MAPK-ERK1/2 signaling, a stretch-induced responsive pathway. The same tensile strain applied to mouse oligodendrocytes in primary culture induced a profound damage to cell morphology, partial cell loss, and a decrease of myelin protein expression. The lower tensile strain of 20% also caused cell loss and the remaining oligodendrocytes appeared retracted with decreased myelin protein expression. Finally, high-magnitude tensile strain applied to 158N oligodendroglial cells altered myelin protein expression, dampened MAPK-ERK1/2 and MAPK-p38 signaling, and enhanced the production of reactive oxygen species. The latter was accompanied by increased protein oxidation and an alteration of anti-oxidant defense that was strain magnitude-dependent. In conclusion, mechanical stretch of high magnitude provokes axonal injury with significant alterations in oligodendrocyte biology that could initiate demyelination. Electronic supplementary material The online version of this article (10.1007/s12035-018-1372-6) contains supplementary material, which is available to authorized users.
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- 2018
33. A novel model of trauma-induced cerebellar injury and myelin loss in mouse organotypic cerebellar slice cultures using live imaging
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Mehrnaz Jafarian-Tehrani, Delphine Meffre, Charbel Massaad, and Gemma Llufriu-Dabén
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cerebellum ,Traumatic brain injury ,Green Fluorescent Proteins ,Mice, Transgenic ,Neuroprotection ,03 medical and health sciences ,chemistry.chemical_compound ,Myelin ,Purkinje Cells ,0302 clinical medicine ,Organ Culture Techniques ,Live cell imaging ,Brain Injuries, Traumatic ,Medicine ,Animals ,Propidium iodide ,Myelin Sheath ,business.industry ,General Neuroscience ,Optical Imaging ,Etazolate ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,chemistry ,business ,030217 neurology & neurosurgery ,Ex vivo ,Propidium - Abstract
Background Traumatic brain injury (TBI) induces significant cognitive deficits correlated with white matter injury, involving both axonal and myelin damage. Several models of TBI ex vivo are available to mimic focal impact on brain tissue. However, none of them addressed the study of trauma-induced myelin damage. New method The aim of this study was to set up a novel ex vivo weight-drop model on organotypic cultures obtained from mouse cerebellum, a highly myelinated structure, in order to study the temporal evolution of cerebellar lesion and demyelination. The extent of injury was measured by propidium iodide (PI) fluorescence and demyelination was evaluated by loss of GFP-fluorescence in cerebellar slices from PLP-eGFP mice. Results Live imaging of slices showed an increase of PI-fluorescence and a significant loss of GFP-fluorescence at 6 h, 24 h and 72 h post-injury. At the impact site, we observed a loss of Purkinje cells and myelin sheaths with a marked loss of myelin protein MBP at 72 h following injury. Etazolate, a known protective compound, was able to reduce both the PI-fluorescence increase and the loss of GFP-fluorescence, emphasizing its protective effect on myelin loss. Comparison with existing methods and conclusions In line with the existing models of focal injury, we characterized trauma-induced cerebellar lesion with an increase of PI fluorescence by live imaging. Our findings describe a novel tool to study trauma-induced myelin damage in cerebellar slices and to test biomolecules of therapeutic interest for myelin protection.
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- 2018
34. Antidepressive effects of targeting ELK-1 signal transduction
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Juan Pablo Lopez, Elsa Isingrini, Marie-Anne El Khoury, Naguib Mechawar, Chloé Guinaudie, Alejandro Orrico, Raphaele Mongredien, Jocelyne Caboche, Carlos Eduardo Macedo, Fabio Marti, Yiu C. Tse, Wojciech Jaworski, Bruno Giros, Severine Farley, Tak Pan Wong, Gustavo Turecki, Vincent Vialou, Kallia Apazoglou, Elise Morice, Ferah Yildirim, Franck Louis, Julien Grenier, Sophie Gautron, Laurent Groc, Ariane Bochereau, Sylvie Dumas, El Chérif Ibrahim, Raoul Belzeaux, Lenka Mikasova, Victor Gorgievski, Alexandre Barbé, Charbel Massaad, Eleni T. Tzavara, Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), McGill University = Université McGill [Montréal, Canada], FondaMental Foundation, Fondation de Coopération Scientifique Hôpital, A. Chenevier, Douglas Mental Health University Institute [Montréal], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroplasticité et thérapie des addictions (ERL 3649), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Oramacell [Paris, France], Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies psychiatriques = Pathophysiology of Psychiatric Disorders (NPS-07), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Pôle de Psychiatrie Universitaire Solaris, Marseille, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Research Center of the Douglas Mental Health University Institute, PMSNC, Interdisciplinary Institute for Neuroscience, Régulation de la transcription et maladies génétiques (RTMG), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie et comportements = Neurophysiology and Behavior (NPS-06), Neurobiologie des processus adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), McGill University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pôle de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud )-CHU Marseille, Fondation FondaMental [Créteil], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and caboche, jocelyne
- Subjects
Adult ,Male ,0301 basic medicine ,MAPK/ERK pathway ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV]Life Sciences [q-bio] ,Druggability ,Hippocampus ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Elk-1 ,0302 clinical medicine ,Downregulation and upregulation ,ELK1 ,Animals ,Humans ,Medicine ,RNA, Messenger ,dentate gyrus ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Transcription factor ,ets-Domain Protein Elk-1 ,chronic stress ,Neuronal Plasticity ,Behavior, Animal ,Depression ,General Commentary ,business.industry ,Kinase ,General Medicine ,Middle Aged ,Antidepressive Agents ,adult neurogenesis ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,[SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health ,Synaptic plasticity ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Signal transduction ,business ,Neuroscience ,Stress, Psychological ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
International audience; Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.
- Published
- 2018
35. The Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis
- Author
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Ludmila Juricek, Charbel Massaad, Frédéric Charbonnier, Mehdi Hichor, Ingrid Laurendeau, Eric Pasmant, Etienne-Emile Baulieu, Ivan Bièche, Marc Herbin, Xavier Coumoul, Frédérique Larousserie, Mathieu Beraneck, Laure Weill, Nicolas Ortonne, Nirmal Kumar Sampathkumar, Ghjuvan’Ghjacumu Shackleford, Delphine Meffre, Aline Chevallier, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Mécanismes Adaptatifs et Evolution (MECADEV), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), ANR-13-CESA-0005,TOXAhBRAIN,Rôle du récepteur Ah et effets de ses ligands sur le système nerveux(2013), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
- Subjects
Male ,0301 basic medicine ,AHR ,Schwann cell ,Apoptosis ,medicine.disease_cause ,Nerve Sheath Neoplasms ,Malignant transformation ,neurofibroma ,Mice ,03 medical and health sciences ,Myelin ,MPNST ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Humans ,Neurofibroma ,Cells, Cultured ,Myelin Sheath ,Regulation of gene expression ,Multidisciplinary ,biology ,Chemistry ,Nerve ,respiratory system ,medicine.disease ,Aryl hydrocarbon receptor ,3. Good health ,respiratory tract diseases ,Wnt/ beta catenin Running title: AHR in Schwann cells ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,PNAS Plus ,Receptors, Aryl Hydrocarbon ,nervous system ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Cancer research ,biology.protein ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Signal transduction ,Carcinogenesis ,Signal Transduction - Abstract
International audience; Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in xenobiotic metabolism. Plexiform neurofibromas (PNFs) can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to existing therapies. These tumors are primarily composed of Schwann cells. In addition to neurofibroma-tosis type 1 (NF1) gene inactivation, further genetic lesions are required for malignant transformation. We have quantified the mRNA expression levels of AHR and its associated genes in 38 human samples. We report that AHR and the biosynthetic enzymes of its en-dogenous ligand are overexpressed in human biopsies of PNFs and MPNSTs. We also detect a strong nuclear AHR staining in MPNSTs. The inhibition of AHR by siRNA or antagonists, CH-223191 and tri-methoxyflavone, induces apoptosis in human MPNST cells. Since AHR dysregulation is observed in these tumors, we investigate AHR involvement in Schwann cell physiology. Hence, we studied the role of AHR in myelin structure and myelin gene regulation in Ahr −/− mice during myelin development. AHR ablation leads to lo-comotion defects and provokes thinner myelin sheaths around the axons. We observe a dysregulation of myelin gene expression and myelin developmental markers in Ahr −/− mice. Interestingly, AHR does not directly bind to myelin gene promoters. The inhibition of AHR in vitro and in vivo increased β-catenin levels and stimulated the binding of β-catenin on myelin gene promoters. Taken together, our findings reveal an endogenous role of AHR in peripheral myeli-nation and in peripheral nerve sheath tumors. Finally, we suggest a potential therapeutic approach by targeting AHR in nerve tumors. AHR | myelin | nerve | MPNST | neurofibroma
- Published
- 2018
36. WITHDRAWN: Oxysterols and phytosterols in human health
- Author
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Luigi Iuliano, Charbel Massaad, and Gérard Lizard
- Subjects
0301 basic medicine ,03 medical and health sciences ,Human health ,030104 developmental biology ,Chemistry ,Organic Chemistry ,Cell Biology ,Computational biology ,Molecular Biology ,Biochemistry - Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/ 10.1016/j.chemphyslip.2017.08.003. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
- Published
- 2017
37. Oxysterols and phytosterols in human health
- Author
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Luigi Iuliano, Charbel Massaad, Gérard Lizard, Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon] ( BIO-PEROXIL ), Université de Bourgogne ( UB ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Medico-Surgical Sciences and Biotechnologies [Latina, Italy], Vascular Biology & Mass Spectrometry Laboratory [Latina, Italy], Sapienza - Università di Roma [Italy]-Sapienza - Università di Roma [Italy], Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon] (BIO-PEROXIL), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), LIZARD, Gérard, Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Bourgogne ( UB ) -Université Bourgogne Franche-Comté ( UBFC ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS )
- Subjects
0301 basic medicine ,cardiovascular diseases ,humans ,neoplasms ,neurodegenerative diseases ,osteoporosis ,oxysterols ,phytosterols ,biochemistry ,molecular biology ,organic chemistry ,cell biology ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Chemistry ,Organic Chemistry ,Cell Biology ,Bioinformatics ,Biochemistry ,03 medical and health sciences ,Human health ,030104 developmental biology ,0302 clinical medicine ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Molecular Biology ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience; no abstract
- Published
- 2017
38. AhR-deficiency as a cause of demyelinating disease and inflammation
- Author
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Thorfinn T. Riday, Justine Lanzini, Robert Barouki, Frank Letourneur, Olivier Laprévote, Nicolas Auzeil, Florent Dumont, Julie Carcaud, Charbel Massaad, Cendra Agulhon, Alice Pelhaitre, Xavier Coumoul, Aline Chevallier, Ludmila Juricek, Mathieu Beraneck, Sébastien Jacques, Beraneck, Mathieu, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Glia-Glia and Glia-Neuron Interactions in Neurophysiopathology Group (FR 3636), Fédération de Recherche en Neurosciences (FR 3636), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe Pharmacognosie (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
- Subjects
0301 basic medicine ,Central nervous system ,lcsh:Medicine ,Inflammation ,Article ,Mice ,03 medical and health sciences ,Demyelinating disease ,medicine ,Animals ,Genetic Predisposition to Disease ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Receptor ,lcsh:Science ,Genetic Association Studies ,Myelin Sheath ,Mice, Knockout ,Multidisciplinary ,biology ,Cell adhesion molecule ,lcsh:R ,Optic Nerve ,Aryl hydrocarbon receptor ,medicine.disease ,Phenotype ,3. Good health ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Receptors, Aryl Hydrocarbon ,nervous system ,Astrocytes ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Immunology ,biology.protein ,Cytokines ,Evoked Potentials, Visual ,lcsh:Q ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Inflammation Mediators ,Signal transduction ,medicine.symptom ,Demyelinating Diseases ,Signal Transduction - Abstract
The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.
- Published
- 2017
39. The Spontaneous Autoimmune Neuromyopathy in ICOSL
- Author
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Claire, Briet, Gwladys, Bourdenet, Ute C, Rogner, Chantal, Becourt, Isabelle, Tardivel, Laurent, Drouot, Christophe, Arnoult, Jean-Claude, do Rego, Nicolas, Prevot, Charbel, Massaad, Olivier, Boyer, and Christian, Boitard
- Subjects
costimulation ,ICOS ,type 1 diabetes ,Immunology ,autoimmunity ,ICOSL ,neuropathy ,Original Research ,myopathy - Abstract
Abrogation of ICOS/ICOS ligand (ICOSL) costimulation prevents the onset of diabetes in the non-obese diabetic (NOD) mouse but, remarkably, yields to the development of a spontaneous autoimmune neuromyopathy. At the pathological level, ICOSL−/− NOD mice show stronger protection from insulitis than their ICOS−/− counterparts. Also, the ICOSL−/− NOD model carries a limited C57BL/6 region containing the Icosl nul mutation, but, in contrast to ICOS−/− NOD mice, no gene variant previously reported as associated to NOD diabetes. Therefore, we aimed at providing a detailed characterization of the ICOSL−/− NOD model. The phenotype observed in ICOSL−/− NOD mice is globally similar to that observed in ICOS−/− and ICOS−/−ICOSL−/− double-knockout NOD mice, manifested by a progressive locomotor disability first affecting the front paws as observed by catwalk analysis and a decrease in grip test performance. The pathology remains limited to peripheral nerve and striated muscle. The muscle disease is characterized by myofiber necrosis/regeneration and an inflammatory infiltrate composed of CD4+ T-cells, CD8+ T-cells, and myeloid cells, resembling human myositis. Autoimmune neuromyopathy can be transferred to NOD.scid recipients by CD4+ but not by CD8+ T-cells isolated from 40-week-old female ICOSL−/− NOD mice. The predominant role of CD4+ T-cells is further demonstrated by the observation that neuromyopathy does not develop in CIITA−/−ICOSL−/− NOD in contrast to β2microglobulin−/−ICOSL−/− NOD mice. Also, the cytokine profile of CD4+ T-cells infiltrating muscle and nerve of ICOSL−/− NOD mice is biased toward a Th1 pattern. Finally, adoptive transfer experiments show that diabetes development requires expression of ICOSL, in contrast to neuromyopathy. Altogether, the deviation of autoimmunity from the pancreas to skeletal muscles in the absence of ICOS/ICOSL signaling in NOD mice is strictly dependent on CD4+ T-cells, leads to myofiber necrosis and regeneration. It provides the first mouse model of spontaneous autoimmune myopathy akin to human myositis.
- Published
- 2016
40. Optimal use of statistical methods to validate reference gene stability in longitudinal studies
- Author
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Charbel Massaad, Julien Grenier, Venkat Krishnan Sundaram, Nirmal Kumar Sampathkumar, Bodescot, Myriam, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Candidate gene ,Statistics as Topic ,Gene Expression ,Nervous System ,Database and Informatics Methods ,Mathematical and Statistical Techniques ,0302 clinical medicine ,Cerebellum ,Reference genes ,Statistics ,Medicine and Health Sciences ,Longitudinal Studies ,Mathematics ,Cerebral Cortex ,Multidisciplinary ,Applied Mathematics ,Simulation and Modeling ,Rank (computer programming) ,Brain ,Reference Standards ,Variable (computer science) ,Spinal Cord ,Research Design ,Physical Sciences ,Medicine ,Analysis of variance ,Anatomy ,Sequence Analysis ,Algorithms ,Research Article ,Bioinformatics ,Science ,Stability (learning theory) ,Sequence Databases ,Research and Analysis Methods ,03 medical and health sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetics ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RNA, Messenger ,Statistical Methods ,Analysis of Variance ,Gene Expression Profiling ,Reproducibility of Results ,Biology and Life Sciences ,Myelin Basic Protein ,Mice, Inbred C57BL ,Gene expression profiling ,Neuroanatomy ,Biological Databases ,030104 developmental biology ,Genes ,Ranking ,Pairwise comparison ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Multiple statistical approaches have been proposed to validate reference genes in qPCR assays. However, conflicting results from these statistical methods pose a major hurdle in the choice of the best reference genes. Recent studies have proposed the use of a minimum of three different methods but there is no consensus on how to interpret conflicting results. Researchers resort to averaging the ranks or attributing a weighted rank to candidate genes. However, we report here that the suitability of these validation methods can be influenced by the experimental setting. Therefore, averaging the ranks can lead to suboptimal assessment of stable reference genes if the method used is not suitable for analysis. As the respective approaches of these statistical methods are different, a clear understanding of the fundamental assumptions and the parameters that influence the reference gene stability calculation is necessary. In this study, the stability of 10 candidate reference genes (Actb, Gapdh, Tbp, Sdha, Pgk1, Ppia, Rpl13a, Hsp60, Mrpl10, Rps26) was assessed using four common statistical approaches (GeNorm, NormFinder, Coefficient of Variation or CV analysis and Pairwise ΔCt method) in a longitudinal experimental setting. We used the development of the cerebellum and the spinal cord of mice as a model to assess the suitability of these statistical methods for reference gene validation. GeNorm and the Pairwise ΔCt were found to be ill suited due to a fundamental assumption in their stability calculations. Highly correlated genes were given better stability ranks despite significant overall variation. NormFinder fares better but the presence of highly variable genes influences the ranking of all genes because of the algorithm’s construct. CV analysis estimates overall variation, but it fails to consider variation across groups. We thus highlight the assumptions and potential pit-falls of each method using our longitudinal data. Based on our results, we have devised a workflow combining NormFinder, CV analysis along with visual representation of mRNA fold changes and one-way ANOVA for validating reference genes in longitudinal studies. This workflow proves to be more robust than any of these methods used individually. Additional Information Competing Interests – The authors declare no conflict of interest.
- Published
- 2019
41. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease
- Author
-
Filippo Martinelli-Boneschi, Mary Encarnacion, Weihong Song, Jacqueline A. Quandt, Federica Esposito, Carles Vilariño-Güell, Laura Leyva, Denis Gris, Elena Urcelay, Jordan Follett, Angela Deutschländer, Elisabetta Mascia, Alexander Zimprich, Tobias Zrzavy, Guillermo Izquierdo, Fuencisla Matesanz, Anthony Traboulsee, Patricia Urbaneja-Romero, Alfredo Antigüedad, Andrea Zauli, Zhe Wang, Jorge Mena, Antonio Alcina, Charbel Massaad, Bruno Herculano, Koen Vandenbroeck, A. Dessa Sadovnick, Jesús Ortega-Pinazo, Maria G. Criscuoli, Cecily Q. Bernales, Irene M. Yee, Eva M. Reinthaler, Laura Espino-Paisán, Canada Research Chairs, Michael Smith Foundation for Health Research, Canadian Institutes of Health Research, Vancouver Coastal Health Research Institute, Milan & Maureen Ilich Foundation, Vancouver Foundation, Red Española de Esclerosis Múltiple, Ministerio de Economía y Competitividad (España), and Junta de Andalucía
- Subjects
Male ,Cancer Research ,Candidate gene ,QH426-470 ,alpha-T-catenin ,0302 clinical medicine ,Exome ,cell-activation ,immune-responses ,Myelin Sheath ,Genetics (clinical) ,Exome sequencing ,Neurons ,Genetics ,0303 health sciences ,Neurodegeneration ,Wnt signaling pathway ,ion channels ,Inflammasome ,inflammatory response ,Middle Aged ,complement anaphylatoxin C3AA ,Pedigree ,3. Good health ,Codon, Nonsense ,Female ,medicine.drug ,Adult ,signaling pathway ,Multiple Sclerosis ,Biology ,NA+/CA2+ exchanger ,Young Adult ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Inflammation ,Innate immune system ,Multiple sclerosis ,Correction ,medicine.disease ,Human genetics ,diagnostic-criteria ,Nerve Degeneration ,central-nervous-system ,Transcriptome ,030217 neurology & neurosurgery ,Demyelinating Diseases - Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients., This research was undertaken thanks to funding from the Canada Research Chair program (950-228408), Michael Smith Foundation for Health Research (16827), the Canadian Institutes of Health Research (MOP-137051), the Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation (11-32095000), and the Vancouver Foundation (ADV14-1597) to CVG. Additional funds were provided by >Red Española de Esclerosis Múltiple (REEM)> (grant to KV was RD12/0032/0013; RETICS, ISCIII), Project FIS PI13/ 0879 Grant RETICS-REEM RD07/0060/0019; Ministerio de Economía y Competitividad-FEDER SAF2016-80595-C2-1-P to AA and FM, Junta de Andalucia-FEDER to FM, and the Ricerca Finalizzata of the Italian Ministry of Health (RF-2011-02350347). EU, LL, LEP, and PUR are members of the Spanish Network of Multiple Sclerosis REEM RD16/0015/0010, supported by Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofunded by European Regional Development Fund). LL holds a Nicolas Monardes contract (C-0014-2015) from the Andalusian Health Ministry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Published
- 2019
42. Differential regulation of Wnt/beta-catenin signaling by Liver X Receptors in Schwann cells and oligodendrocytes
- Author
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Ghjuvan’Ghjacumu Shackleford, Julien Grenier, Delphine Meffre, Charbel Massaad, Philippe Liere, and Joelle Makoukji
- Subjects
Oxysterol ,Schwann cell ,Biology ,Biochemistry ,Cell Line ,Mice ,Myelin ,polycyclic compounds ,medicine ,Animals ,Liver X receptor ,Wnt Signaling Pathway ,Myelin Sheath ,beta Catenin ,Liver X Receptors ,Mice, Knockout ,Pharmacology ,Wnt signaling pathway ,Brain ,Orphan Nuclear Receptors ,Sciatic Nerve ,Hydroxycholesterols ,Oligodendrocyte ,Cell biology ,Oligodendroglia ,Sterols ,medicine.anatomical_structure ,Gene Expression Regulation ,nervous system ,Nuclear receptor ,TCF3 ,lipids (amino acids, peptides, and proteins) ,Schwann Cells ,Myelin P0 Protein ,Myelin Proteins - Abstract
Oxysterols are reactive molecules generated by the oxidation of cholesterol. Their implication in cholesterol homeostasis and in the progression of neurodegenerative disorders is well known. Here, we study the role of oxysterols and their nuclear receptors, Liver X Receptor (LXR), in myelinating glial cells of the central and peripheral nervous systems. First, we show by gas chromatography/mass spectrometry that the brain, sciatic nerve, oligodendrocytes and Schwann cells contain 24(S)-hydroxycholesterol, 25-hydroxycholesterol (25-OH) and 27-hydroxycholesterol, and they express their biosynthetic enzymes. We observed a differential effect of 25-OH toward myelin genes (MPZ and PMP22) expression: 25-OH inhibits MPZ and PMP22 in Schwann cell line but not in oligodendrocyte cell line. Importantly, the invalidation of LXR in mice enhanced MPZ and PMP22 transcripts expression in the sciatic nerve, but inhibited their expression in the brain. We have previously reported that Wnt signaling pathway is crucial for myelin gene expression. We show that the transcripts of Wnt components (Disheveled, TCF3, beta-catenin) are strongly repressed by oxysterols in Schwann cells but are activated in oligodendrocytes. Furthermore, we show by immunofluorescent labeling that beta-catenin is re-localized on the level of the Golgi apparatus of Schwann cells after incubation with 25-OH. We did not observe such an unusual localization of beta-catenin in oligodendrocytes. Our findings reveal a complex cross-talk between LXR and Wnt/beta-catenin pathway in myelinating glial cells.
- Published
- 2013
43. Paraquat Induces Peripheral Myelin Disruption and Locomotor Defects: Crosstalk with LXR and Wnt Pathways
- Author
-
Victor Gorgievski, Patrice X. Petit, Julia Montanaro, Didier Borderie, Eleni T. Tzavara, Frédéric Charbonnier, Assaad A. Eid, Nirmal Kumar Sampathkumar, Charbel Massaad, Mehdi Hichor, and Julien Grenier
- Subjects
0301 basic medicine ,Nervous system ,Male ,Paraquat ,Physiology ,Clinical Biochemistry ,Biology ,medicine.disease_cause ,Biochemistry ,Protein Aggregation, Pathological ,Cell Line ,Protein Carbonylation ,03 medical and health sciences ,Myelin ,Mice ,0302 clinical medicine ,Gene expression ,medicine ,Animals ,Liver X receptor ,Molecular Biology ,Wnt Signaling Pathway ,Myelin Sheath ,General Environmental Science ,Liver X Receptors ,chemistry.chemical_classification ,Reactive oxygen species ,Herbicides ,Wnt signaling pathway ,Cell Biology ,medicine.disease ,Cell biology ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,Peripheral neuropathy ,chemistry ,Gene Expression Regulation ,General Earth and Planetary Sciences ,Lipid Peroxidation ,Schwann Cells ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Oxidative stress ,Myelin Proteins ,Demyelinating Diseases - Abstract
Paraquat (PQT), a redox-active herbicide, is a free radical-producing molecule, causing damage particularly to the nervous system; thus, it is employed as an animal model for Parkinson's disease. However, its impact on peripheral nerve demyelination is still unknown. Our aim is to decipher the influence of PQT-induced reactive oxygen species (ROS) production on peripheral myelin.We report that PQT provokes severe locomotor and sensory defects in mice. PQT elicited an oxidative stress in the nerve, resulting in an increase of lipid peroxidation and protein carbonylation, despite the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defenses. We observed a dramatic disorganization of myelin sheaths in the sciatic nerves, dysregulation of myelin gene expression, and aggregation of myelin proteins, a hallmark of demyelination. PQT altered myelin gene expression via liver X receptor (LXR) signaling, a negative regulator of peripheral myelin gene expression through its dialog with the Wnt/β-catenin pathway. PQT prevented β-catenin binding on myelin gene promoters, resulting in the inhibition of Wnt/β-catenin-dependent myelin gene expression. Wnt pathway activation by LiCl dampened the deleterious effects of PQT. LiCl blocked PQT-induced oxidative stress and reduced Schwann cell death. LiCl+PQT-treated mice had normal sensorimotor behaviors and a usual nerve structure.We reveal that PQT damages the sciatic nerve by generating an oxidative stress, dysregulating LXR and Wnt/β-catenin pathways. The activation of Wnt signaling by LiCl reduced the deleterious effects of PQT on the nerve.We demonstrate that PQT instigates peripheral nerve demyelinating neuropathies by enhancing ROS production and deregulating LXR and Wnt pathways. Stimulating Wnt pathway could be a therapeutic strategy for neuropathy treatment. Antioxid. Redox Signal. 27, 168-183.
- Published
- 2016
44. Oxidative Stress in Diabetic Neuropathy: Strategies for Treatment
- Author
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Assaad A. Eid, Stephanie Eid, and Charbel Massaad
- Subjects
medicine.medical_specialty ,Pediatrics ,Diabetic neuropathy ,business.industry ,Incidence (epidemiology) ,Public health ,Metabolic risk ,medicine.disease ,medicine.disease_cause ,Diabetes Therapy ,Diabetes mellitus ,Medicine ,business ,Oxidative stress ,Cause of death - Abstract
Diabetes is a major public health problem. In 2014, the global prevalence of diabetes was estimated to be 9% among adults aged 18 years old and above. The incidence of diabetes has increased immensely in the past 10 years. The World Health Organization (WHO) projects that diabetes will be the seventh leading cause of death in 2030. This alone makes it an epidemic disease. Diabetes is associated with a number of metabolic risk factors that contribute to a high rate of micro and macrovascular events. One of the most common and debilitating complications associated with diabetes is Diabetic Neuropathy (DN); it affects about 10% of patients newly diagnosed with diabetes and more than 50% of patients with longstanding diabetes.
- Published
- 2016
45. Lithium enhances remyelination of peripheral nerves
- Author
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Ruth M. Stassart, Michael Schumacher, Delphine Meffre, Etienne-Emile Baulieu, Robert Fledrich, Sophie Bernard, Martin Belle, Ghjuvan’ Ghjacumu Shackleford, Julien Branchu, Joelle Makoukji, Marie Goulard, Catherine de Waele, Frédéric Charbonnier, Julien Grenier, Cosima Fonte, Charbel Massaad, and Michael W. Sereda
- Subjects
Male ,inorganic chemicals ,Biology ,Neuroprotection ,Placebos ,Glycogen Synthase Kinase 3 ,Mice ,Myelin ,chemistry.chemical_compound ,GSK-3 ,medicine ,Animals ,Peripheral Nerves ,Remyelination ,GSK3B ,Myelin Sheath ,Cell Nucleus ,Glycogen Synthase Kinase 3 beta ,Multidisciplinary ,Biological Sciences ,medicine.disease ,Sciatic Nerve ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,nervous system ,chemistry ,Crush injury ,Lithium chloride ,Schwann Cells ,Sciatic nerve ,Lithium Chloride ,Myelin P0 Protein ,Proto-Oncogene Proteins c-akt ,Neuroscience ,Signal Transduction - Abstract
Glycogen synthase kinase 3β (GSK3β) inhibitors, especially the mood stabilizer lithium chloride, are also used as neuroprotective or anti-inflammatory agents. We studied the influence of LiCl on the remyelination of peripheral nerves. We showed that the treatment of adult mice with LiCl after facial nerve crush injury stimulated the expression of myelin genes, restored the myelin structure, and accelerated the recovery of whisker movements. LiCl treatment also promoted remyelination of the sciatic nerve after crush. We also demonstrated that peripheral myelin gene MPZ and PMP22 promoter activities, transcripts, and protein levels are stimulated by GSK3β inhibitors (LiCl and SB216763) in Schwann cells as well as in sciatic and facial nerves. LiCl exerts its action in Schwann cells by increasing the amount of β-catenin and provoking its nuclear localization. We showed by ChIP experiments that LiCl treatment drives β-catenin to bind to T-cell factor/lymphoid-enhancer factor response elements identified in myelin genes. Taken together, our findings open perspectives in the treatment of nerve demyelination by administering GSK3β inhibitors such as lithium.
- Published
- 2012
46. β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites
- Author
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Lucie M. Laqueuvre, Eliette Bonnefoy, Charbel Massaad, Zeyni Mansuroglu, Jean-Jacques Panthier, Lionel Luron, Dominique Simon, Vasco Marcato, Sylvie Souès, Marie Flamand, Homéostasie cellulaire et cancer - Reprogrammation des réponses biologiques et thérapies alternatives (U1007), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Descartes - Paris 5 (UPD5), Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Virologie Structurale, Toxicologie, Pharmacologie et Signalisation Cellulaire (U1124), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Agence Nationale de la Recherche (ANR)ANR-11-BSV3-007, Eliette Bonnefoy, Marie Flamand, Jean-Jacques Panthier.The DIM-Malinf project from Région Ile-de-France, Vasco Marcato, ANR-11-BSV3-0007, GenRift, Identification de voies cellulaires et de gènes clés pour la pathogénicité et la résistance au virus de la fièvre de la Vallée du Rift(2011), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virologie Structurale - Structural Virology, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-BSV3-0007,GenRift,Identification de voies cellulaires et de gènes clés pour la pathogénicité et la résistance au virus de la fièvre de la Vallée du Rift(2011), PANTHIER, Jean-Jacques, BLANC - Identification de voies cellulaires et de gènes clés pour la pathogénicité et la résistance au virus de la fièvre de la Vallée du Rift - - GenRift2011 - ANR-11-BSV3-0007 - BLANC - VALID, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
- Subjects
MESH: Signal Transduction ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,MESH: beta Catenin ,Glycogen Synthase Kinase 3 ,Mice ,0302 clinical medicine ,GSK-3 ,MESH: Up-Regulation ,MESH: Animals ,Promoter Regions, Genetic ,beta Catenin ,MESH: Glycogen Synthase Kinase 3 ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,0303 health sciences ,Wnt signaling pathway ,Articles ,3. Good health ,Cell biology ,Up-Regulation ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,MESH: Rift Valley fever virus ,TCF Transcription Factors ,Signal Transduction ,Transcriptional Activation ,T cell ,Biology ,Virus ,03 medical and health sciences ,Immune system ,Downregulation and upregulation ,MESH: Promoter Regions, Genetic ,medicine ,Animals ,Molecular Biology ,MESH: Mice ,[SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology ,030304 developmental biology ,Binding Sites ,MESH: Interferon-beta ,Cell Biology ,Interferon-beta ,Rift Valley fever virus ,Virology ,MESH: T-Lymphocytes ,MESH: Binding Sites ,MESH: Transcriptional Activation ,IRF3 ,030217 neurology & neurosurgery ,MESH: TCF Transcription Factors ,Interferon regulatory factors - Abstract
International audience; Rapid upregulation of interferon beta (IFN-β) expression following virus infection is essential to set up an efficient innate antiviral response. Biological roles related to the antiviral and immune response have also been associated with the constitutive production of IFN-β in naive cells. However, the mechanisms capable of modulating constitutive IFN-β expression in the absence of infection remain largely unknown. In this work, we demonstrate that inhibition of the kinase glycogen synthase kinase 3 (GSK-3) leads to the upregulation of the constitutive level of IFN-β expression in noninfected cells, provided that GSK-3 inhibition is correlated with the binding of β-catenin to the IFN-β promoter. Under these conditions, IFN-β expression occurred through the T-cell factor (TCF) binding sites present on the IFN-β promoter independently of interferon regulatory factor 3 (IRF3). Enhancement of the constitutive level of IFN-β per se was able to confer an efficient antiviral state to naive cells and acted in synergy with virus infection to stimulate virus-induced IFN-β expression. Further emphasizing the role of β-catenin in the innate antiviral response, we show here that highly pathogenic Rift Valley fever virus (RVFV) targets the Wnt/β-catenin pathway and the formation of active TCF/β-catenin complexes at the transcriptional and protein level in RVFV-infected cells and mice.
- Published
- 2015
47. Liver X Receptors differentially modulate central myelin gene mRNA levels in a region-, age- and isoform-specific manner
- Author
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Ghjuvan’ Ghjacumu Shackleford, Walid Abi Habib, Delphine Meffre, Julien Grenier, and Charbel Massaad
- Subjects
0301 basic medicine ,Gene isoform ,Central Nervous System ,Male ,Hydrocarbons, Fluorinated ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Central nervous system ,Biology ,Biochemistry ,Corpus Callosum ,03 medical and health sciences ,Myelin ,Mice ,0302 clinical medicine ,Endocrinology ,Cerebellum ,Gene expression ,medicine ,Animals ,Protein Isoforms ,RNA, Messenger ,Remyelination ,Liver X receptor ,Molecular Biology ,Myelin Sheath ,Liver X Receptors ,Mice, Knockout ,Sulfonamides ,Gene Expression Regulation, Developmental ,Optic Nerve ,Cell Biology ,Oligodendrocyte ,Cell biology ,Oligodendroglia ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Nuclear receptor ,Spinal Cord ,Immunology ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Liver X Receptors (LXRs) α and β are nuclear receptors able to bind oxidative forms of cholesterol. They play important roles in the central nervous system (CNS), through their implication in a large variety of physiological and pathological processes among which modulation of cholesterol homeostasis and inflammation. Besides, we recently revealed their crucial role in myelination and remyelination in the cerebellum. Given the pleiotropic effects of such receptors on CNS functioning, we studied here the influence of LXRs on myelin gene mRNA accumulation in the major myelinated regions of the CNS in vivo. We show that both LXR isoforms differentially affect mRNA amount of myelin genes (PLP and MBP) in highly myelinated structures such as spinal cord, corpus callosum, optic nerve and cerebellum. In the adult, LXR activation by the synthetic agonist TO901317 significantly increases myelin gene mRNA amount in the cerebellum but not in the other regions studied. Invalidation of the sole LXRβ isoform leads to decreased PLP and MBP mRNA levels in all the structures except the spinal cord, while the knock out of both isoforms (LXR dKO) decreases myelin gene mRNA amounts in all the regions tested except the corpus callosum. Interestingly, during myelination process (post-natal day 21), both cerebellum and optic nerve display a decrease in myelin gene mRNA levels in LXR dKO mice. Concomitantly, PLP and MBP mRNA accumulation in the spinal cord is increased. Relative expression level of LXR isoforms could account for the differential modulation of myelin gene expression in the CNS. Altogether our results suggest that, within the CNS, each LXR isoform differentially influences myelin gene mRNA levels in a region- and age-dependant manner, participating in the fine regulation of myelin gene expression.
- Published
- 2015
48. Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-α Expression in Breast Cancer Cells
- Author
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Robert Barouki, Etienne Blanc, Nathalie M. Mazure, Fabrice Lecuru, Marie-Claude Fulchignoni-Lataud, Marie-Aude Le Frere Belda, Anne Dreiem, Thérèse Hervèe Mayi, Charbel Massaad, Vincent Favaudon, Liliane Massaad-Massade, Ramzi Seifeddine, Laboratoire de Détection et de Géophysique (CEA) (LDG), DAM Île-de-France (DAM/DIF), Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), IFR50, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Faculté de Médecine Nice, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Génotoxicologie, signalisation et radiothérapie expérimentale, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique moléculaire, Régulation de la transcription et maladies génétiques (RTMG), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Stéroïdes et système nerveux : physiopathologie moléculaire et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris-Sud, Université Paris-Sud - Paris 11 (UP11), Toxicologie Moleculaire (U490), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Détection et de Géophysique (CEA) ( LDG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Faculté de Médecine Nice, Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Régulation de la transcription et maladies génétiques ( RTMG ), Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ), Toxicologie Moleculaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Faculté de Médecine Nice, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie
- Subjects
Cancer Research ,Hypoxia-Inducible Factor 1 ,MESH : Molecular Sequence Data ,MESH : RNA, Messenger ,Transcription, Genetic ,MESH : Immunohistochemistry ,MESH: Cell Hypoxia ,Electrophoretic Mobility Shift Assay ,MESH: Cell Cycle ,RNA polymerase II ,MESH : Blotting, Western ,MESH : Breast Neoplasms ,MESH: Base Sequence ,MESH : RNA, Small Interfering ,MESH: Down-Regulation ,MESH : Down-Regulation ,0302 clinical medicine ,Transcription (biology) ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,Enhancer binding ,MESH: RNA, Small Interfering ,Gene expression ,MESH: CCAAT-Enhancer-Binding Protein-alpha ,MESH : CCAAT-Enhancer-Binding Protein-alpha ,RNA, Small Interfering ,Promoter Regions, Genetic ,0303 health sciences ,Gene knockdown ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Cycle ,MESH : Reverse Transcriptase Polymerase Chain Reaction ,Immunohistochemistry ,Cell Hypoxia ,3. Good health ,MESH: Promoter Regions (Genetics) ,Oncology ,MESH : Electrophoretic Mobility Shift Assay ,030220 oncology & carcinogenesis ,MESH: Cell Growth Processes ,MESH : Cell Hypoxia ,MESH : Transfection ,Subcellular Fractions ,medicine.medical_specialty ,MESH : Hypoxia-Inducible Factor 1, alpha Subunit ,MESH: Cell Line, Tumor ,Blotting, Western ,Molecular Sequence Data ,MESH : Deferoxamine ,Down-Regulation ,Breast Neoplasms ,Cell Growth Processes ,MESH : Subcellular Fractions ,Deferoxamine ,Biology ,Transfection ,MESH: Hypoxia-Inducible Factor 1, alpha Subunit ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,MESH : Cell Cycle ,CCAAT-Enhancer-Binding Protein-alpha ,medicine ,Humans ,MESH: Blotting, Western ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RNA, Messenger ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Transcription factor ,MESH: RNA, Messenger ,030304 developmental biology ,MESH: Humans ,MESH: Molecular Sequence Data ,Base Sequence ,MESH : Cell Line, Tumor ,MESH: Transcription, Genetic ,MESH: Transfection ,MESH : Humans ,MESH : Transcription, Genetic ,MESH: Immunohistochemistry ,MESH: Deferoxamine ,Hypoxia-Inducible Factor 1, alpha Subunit ,MESH : Promoter Regions (Genetics) ,Molecular biology ,Endocrinology ,HIF1A ,MESH : Cell Growth Processes ,MESH: Subcellular Fractions ,MESH: Electrophoretic Mobility Shift Assay ,biology.protein ,MESH : Base Sequence ,MESH: Breast Neoplasms - Abstract
International audience; The transcription factor CCAAT/enhancer binding protein-alpha (C/EBP alpha) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBP alpha mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-beta-D-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBP alpha mRNA by approximately 30%. C/EBP alpha gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (-522; -527 bp), which binds to hypoxia-inducible factor (HIF)-1 alpha, as essential for down-regulation of C/EBP alpha transcription in hypoxia. Immunocytochemical analysis showed that C/EBP alpha was localized in the nucleus at 21% O(2), but was mostly cytoplasmic under 1% O(2). Knockdown of HIF-1 alpha by RNAi restored C/EBP alpha to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBP alpha and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBP alpha expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBP alpha in hypoxia is mediated by HIF-1.
- Published
- 2008
49. Opposite effects of CBP and p300 in glucocorticoid signaling in astrocytes
- Author
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Julien Grenier, Amalia Trousson, Michael Schumacher, Cosima Fonte, and Charbel Massaad
- Subjects
medicine.medical_specialty ,Cell type ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biology ,Transfection ,Models, Biological ,Biochemistry ,Rats, Sprague-Dawley ,Transactivation ,Receptors, Glucocorticoid ,Endocrinology ,Glucocorticoid receptor ,Internal medicine ,Chlorocebus aethiops ,Coactivator ,medicine ,Animals ,Receptor ,Molecular Biology ,Cells, Cultured ,Regulation of gene expression ,Membrane Proteins ,Cell Biology ,Phosphoproteins ,Rats ,Cell biology ,Gene Expression Regulation ,Nuclear receptor ,Astrocytes ,COS Cells ,Molecular Medicine ,E1A-Associated p300 Protein ,Glucocorticoid ,Signal Transduction ,medicine.drug - Abstract
In the nervous system, glucocorticoid hormones play a major role during development, and they continue to affect functional and structural plasticity throughout life. Glucocorticoid actions are mediated by their cognate nuclear receptor, the glucocorticoid receptor (GR). The transcriptional activity of the GR is enhanced by the recruitment of one of the transcriptional coactivators of the p160 family (SRCs), which are a docking platform for secondary coactivators like CBP, or its close homologue p300. Here, we investigated the implication of CBP and p300 coactivators in glial cells of the central and peripheral nervous system, namely in primary cultures of astrocytes and in Schwann cells. We show that both coregulators behave differently in either cell type. CBP enhances GR transcriptional activation in astrocytes, and has no effect in Schwann cells, whereas p300 exerts an inhibitory effect in both glial cells. Studies with p300 deletion mutants show that the repressive capacity of p300 is related to its acetyltransferase activity. This work shows striking differences between CBP and p300 actions in astrocytes. Moreover, in astrocytes the opposite effects of CBP and p300 could lead to a balance in the transactivation potency of the GR, in order to fine tune the action of glucocorticoids.
- Published
- 2007
50. IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice
- Author
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Olivier, Biondi, Julien, Branchu, Amina, Ben Salah, Léo, Houdebine, Lise, Bertin, Farah, Chali, Céline, Desseille, Laure, Weill, Gabriel, Sanchez, Camille, Lancelin, Saba, Aïd, Philippe, Lopes, Claude, Pariset, Sylvie, Lécolle, Jocelyn, Côté, Martin, Holzenberger, Christophe, Chanoine, Charbel, Massaad, and Frédéric, Charbonnier
- Subjects
Male ,Mice, Knockout ,Muscular Atrophy, Spinal ,Mice ,Animals ,Humans ,Female ,Mice, Transgenic ,Articles ,Cells, Cultured ,Receptor, IGF Type 1 ,Signal Transduction - Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA. SIGNIFICANCE STATEMENT Recent evidence of IGF-1 axis alteration in spinal muscular atrophy (SMA), a very severe neurodegenerative disease affecting specifically the motor neurons, have triggered a renewed interest in insulin-like growth factor-1 (IGF-1) pathway activation as a potential therapeutic approach for motor neuron diseases. The present study challenges this point of view and brings the alternative hypothesis that reducing rather than enhancing the IGF-1 signaling pathway exerts a neuroprotective effect in SMA. Furthermore, the present data substantiate a newly emerging concept that the modulation of IGF-1 receptor expression is a key event selectively determining the activation level of intracellular pathways that lie downstream of the receptor. This aspect should be considered when designing IGF-1-based treatments for neurodegenerative diseases.
- Published
- 2015
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