15 results on '"Shyuan T. Ngo"'
Search Results
2. A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration
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Rebecca San Gil, Dana Pascovici, Juliana Venturato, Heledd Brown-Wright, Prachi Mehta, Lidia Madrid San Martin, Jemma Wu, Wei Luan, Yi Kit Chui, Adekunle T. Bademosi, Shilpa Swaminathan, Serey Naidoo, Britt A. Berning, Amanda L. Wright, Sean S. Keating, Maurice A. Curtis, Richard L. M. Faull, John D. Lee, Shyuan T. Ngo, Albert Lee, Marco Morsch, Roger S. Chung, Emma Scotter, Leszek Lisowski, Mehdi Mirzaei, and Adam K. Walker
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Science - Abstract
Abstract Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map ( https://shiny.rcc.uq.edu.au/TDP-map/ ). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.
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- 2024
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3. Generation of a human induced pluripotent stem cell line (UQi001-A-1) edited with the CRISPR-Cas9 system to carry the heterozygous TARDBP c.1144G > A (p.A382T) missense mutation
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Timothy J. Tracey, Leanne Jiang, Melinder K. Gill, Samara N. Ranie, Dmitry A. Ovchinnikov, Ernst J. Wolvetang, and Shyuan T. Ngo
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Biology (General) ,QH301-705.5 - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which the TDP-43 protein is believed to play a central role in disease pathophysiology. Using the CRISPR-Cas9 system, we introduced the heterozygous c.1144G > A (p.A382T) missense mutation in exon 6 of the TARDBP gene into an iPSC line derived from a healthy individual. These edited iPSCs displayed normal cellular morphology, expressed major pluripotency markers, were capable of tri-lineage differentiation, and possessed a normal karyotype.
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- 2023
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4. Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease
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Qiao Ding, Kaamini Kesavan, Kah Meng Lee, Elyse Wimberger, Thomas Robertson, Melinder Gill, Dominique Power, Jeryn Chang, Atefeh T. Fard, Jessica C. Mar, Robert D. Henderson, Susan Heggie, Pamela A. McCombe, Rosalind L. Jeffree, Michael J. Colditz, Massimo A. Hilliard, Dominic C. H. Ng, Frederik J. Steyn, William D. Phillips, Ernst J. Wolvetang, Shyuan T. Ngo, and Peter G. Noakes
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Amyotrophic Lateral Sclerosis ,ALS ,Neuromuscular junction ,MuSK ,Agrin ,Motor neurons ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin (n-agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n-agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n-agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n-agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.
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- 2022
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5. Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1
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Restuadi Restuadi, Frederik J. Steyn, Edor Kabashi, Shyuan T. Ngo, Fei-Fei Cheng, Marta F. Nabais, Mike J. Thompson, Ting Qi, Yang Wu, Anjali K. Henders, Leanne Wallace, Chris R. Bye, Bradley J. Turner, Laura Ziser, Susan Mathers, Pamela A. McCombe, Merrilee Needham, David Schultz, Matthew C. Kiernan, Wouter van Rheenen, Leonard H. van den Berg, Jan H. Veldink, Roel Ophoff, Alexander Gusev, Noah Zaitlen, Allan F. McRae, Robert D. Henderson, Naomi R. Wray, Jean Giacomotto, and Fleur C. Garton
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Motor neurone disease ,MND ,Genome-wide association study ,Computational biology ,Zebrafish ,Neurodegenerative diseases ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. Methods The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N cases = 20,806, N controls = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). Results SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all
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- 2022
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6. Altered TDP-43 Structure and Function: Key Insights into Aberrant RNA, Mitochondrial, and Cellular and Systemic Metabolism in Amyotrophic Lateral Sclerosis
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Leanne Jiang and Shyuan T. Ngo
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amyotrophic lateral sclerosis ,ALS ,TDP-43 ,RNA ,autoregulation ,splicing ,Microbiology ,QR1-502 - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA binding protein-43 (TDP-43) cytoplasmic inclusions. TDP-43 is a ubiquitously expressed RNA binding protein with the capacity to bind over 6000 RNA and DNA targets—particularly those involved in RNA, mitochondrial, and lipid metabolism. Here, we review the unique structure and function of TDP-43 and its role in affecting the aforementioned metabolic processes in ALS. Considering evidence published specifically in TDP-43-relevant in vitro, in vivo, and ex vivo models we posit that TDP-43 acts in a positive feedback loop with mRNA transcription/translation, stress granules, cytoplasmic aggregates, and mitochondrial proteins causing a relentless cycle of disease-like pathology eventuating in neuronal toxicity. Given its undeniable presence in ALS pathology, TDP-43 presents as a promising target for mechanistic disease modelling and future therapeutic investigations.
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- 2022
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7. Use of hip- versus wrist-based actigraphy for assessing functional decline and disease progression in patients with motor neuron disease
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Cory J. Holdom, Jordi W. J. van Unnik, Ruben P. A. van Eijk, Leonard H. van den Berg, Robert D. Henderson, Shyuan T. Ngo, and Frederik J. Steyn
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Neurology ,Neurology (clinical) - Abstract
Background Actigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND. Methods In this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist, n = 97; hip, n = 42) and 56 non-neurological control participants (wrist, n = 56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline. Results Patients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 [− 0.075, − 0.026], variation axis 1 = − 0.073 [− 0.112, − 0.021]). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active: τ = 0.20 vs 0.12; variation axis 1: τ = 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16). Conclusions Actigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND.
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- 2023
8. Muscle and Its Neuromuscular Synapse – Players in the Pathogenesis of Motor Neuron Disease
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Peter G. Noakes, William D. Phillips, Rosalind L. Jeffree, Frederik J. Steyn, Ernst J. Wolvetang, Rob D. Henderson, Pamela A. McCombe, and Shyuan T. Ngo
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Research and Theory ,Leadership and Management ,Review and Exam Preparation ,Fundamentals and skills ,Pharmacology (nursing) ,General Medicine ,LPN and LVN ,General Nursing ,Education - Published
- 2023
9. RNA-seq analysis of skeletal muscle in motor neurone disease cases and controls
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Anna Freydenzon, Shivangi Wani, Vanda Bharti, Leanne M. Wallace, Anjali K. Henders, Pamela A. McCombe, Robert D. Henderson, Frederik J. Steyn, Naomi R. Wray, Shyuan T. Ngo, and Allan F. McRae
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BackgroundAmyotrophic lateral sclerosis (ALS), the most predominant form of Motor Neuron Disease (MND), is a progressive and fatal neurodegenerative condition that spreads throughout the neuromotor system by afflicting upper and lower motor neurons. Lower motor neurons project from the central nervous system and innervate muscle fibres at motor endplates, which degrade over the course of the disease leading to muscle weakness. The direction of neurodegeration from or to the point of neuromuscular junctions and the role of muscle itself in pathogenesis has continued to be a topic of debate in ALS research.MethodsTo assess the variation in gene expression between affected and nonaffected muscle tissue that might lead to this local degeneration of motor units, we generated RNA-seq skeletal muscle transcriptomes from 28 MND cases and 18 healthy controls and conducted differential expression analyses on gene-level counts, as well as an isoform switching analysis on isoform-level counts.ResultsWe identified 52 differentially-expressed genes (Benjamini-Hochberg-adjustedp< 0.05) within this comparison, including 38 protein coding, 9 long non-coding RNA, and 5 pseudogenes. Of protein-coding genes, 31 were upregulated in cases including with notable genes including the collagenicCOL25A1(p= 3.1 × 10−10),SAA1which is released in response to tissue injury (p= 3.6 × 10−5) as well as others of the SAA family, and the actin-encodingACTC1(p= 2.3 × 10−5). Additionally, we identified 17 genes which exhibited a functional isoform switch with likely functional consequences between cases and controls.ConclusionsOur analyses provide evidence of increased tissue generation in MND cases, which likely serve to compensate for the degeneration of motor units and skeletal muscle.
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- 2023
10. Low plasma hyaluronan is associated with faster functional decline in patients with amyotrophic lateral sclerosis
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Cory J Holdom, Shyuan T. Ngo, Pamela A. McCombe, Frederik J. Steyn, and Robert D. Henderson
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Oncology ,medicine.medical_specialty ,Predictive marker ,integumentary system ,business.industry ,Amyotrophic Lateral Sclerosis ,Prognosis ,medicine.disease ,Pathophysiology ,carbohydrates (lipids) ,Glycosaminoglycan ,Extracellular matrix ,Neurology ,Internal medicine ,Disease Progression ,medicine ,Humans ,Biomarker (medicine) ,In patient ,Longitudinal Studies ,Neurology (clinical) ,Hyaluronic Acid ,Functional decline ,Amyotrophic lateral sclerosis ,business - Abstract
Objective: Hyaluronan, a glycosaminoglycan that forms a major constituent of the extracellular matrix, has been shown to be increased in the serum of patients with amyotrophic lateral sclerosis (ALS) with longer disease duration. We sought to determine whether measures of venous hyaluronan may serve as a predictive marker for disease progression in patients with ALS. Methods: Sixty-two patients with ALS, and 59 healthy control participants provided a plasma sample for the assessment of hyaluronan. Hyaluronan was compared against functional measures of disability, disease progression, and survival. Results: Hyaluronan was lower in patients with ALS when compared to healthy controls. Plasma hyaluronan was positively correlated with the change in the revised ALS functional rating scale, ΔFRS. Hyaluronan was also found to improve the prognostic power of the ΔFRS. Conclusion: Hyaluronan may serve as a predictive marker for functional decline in patients with ALS. Longitudinal studies are needed to fully explore the prognostic value of hyaluronan as a biomarker for disease progression, and to improve our understanding of components of the extracellular matrix specific to the pathophysiology of ALS.
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- 2021
11. Lower hypothalamic volume with lower body mass index is associated with shorter survival in patients with amyotrophic lateral sclerosis
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Jeryn, Chang, Thomas B, Shaw, Cory J, Holdom, Pamela A, McCombe, Robert D, Henderson, Jurgen, Fripp, Markus, Barth, Christine C, Guo, Shyuan T, Ngo, and Frederik J, Steyn
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Neurology ,Amyotrophic Lateral Sclerosis ,Weight Loss ,Disease Progression ,Humans ,Neurology (clinical) ,Body Mass Index ,Proportional Hazards Models - Abstract
Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS.We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS (n = 42), patients with AD (n = 167) and non-neurodegenerative disease controls (n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes.Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite (p = 0.58) or hypermetabolism (p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight (p = 0.08) and fat mass (p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07).These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.
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- 2022
12. Profound lipid dysregulation in mutant TDP-43 mice is ameliorated by the glucocerebrosidase 2 inhibitor ambroxol
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Sophia Luikinga, Alexandre Henriques, Shyuan T. Ngo, Thusi Rapasinghe, Jean-Philippe Loeffler, Michael Spedding, and Bradley J. Turner
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The importance of dyslipidemia in amyotrophic lateral sclerosis (ALS) patients is increasingly recognised as a potential key mechanism driving disease onset, progression and survival. Evidence in familial ALS models suggests that lipid composition is significantly affected, however clinically relevant models have yet to be investigated. Using a powerful lipidomic approach, we uncover significant dysregulation of glycosphingolipid (GSL) metabolism in both the spinal cord and skeletal muscles of transgenic TDP-43Q331K mice. Treatment with the selective glucocerebrosidase 2 (GBA2) inhibitor ambroxol at symptom onset significantly improved motor and gait functions in TDP-43Q331K mice. Ambroxol treatment preserved motor neurons and neuromuscular junctions which was associated with modulation of GSL metabolism. Our study establishes significant lipid dysregulation in a clinically relevant model of ALS. Importantly, we show positive therapeutic outcomes in a mouse model of TDP-43 proteinopathy, suggesting that ambroxol may be a promising candidate to treat underlying dyslipidemia and symptoms of ALS.
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- 2022
13. Patient perspectives on digital healthcare technology in care and clinical trials for motor neuron disease : an international survey
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Jochem Helleman, Barbara Johnson, Cory Holdom, Esther Hobson, Deirdre Murray, Frederik J. Steyn, Shyuan T. Ngo, Anjali Henders, Madhura B. Lokeshappa, Johanna M. A. Visser-Meily, Leonard H. van den Berg, Orla Hardiman, Anita Beelen, Chris McDermott, and Ruben P. A. van Eijk
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Technology ,Neurology ,Surveys and Questionnaires ,Amyotrophic Lateral Sclerosis ,Humans ,Neurology (clinical) ,Motor Neuron Disease ,Delivery of Health Care ,Monitoring, Physiologic - Abstract
Introduction To capture the patient’s attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology. Methods We performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients’ attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use. Results In total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements; reporting concerns about the burden and distress of home-monitoring, privacy and data security. Conclusion Most patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care.
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- 2022
14. Repurposing of Trimetazidine for Amyotrophic Lateral Sclerosis: a study in SOD1 G93A mice
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Michela Gloriani, Luisa Pieroni, Cristiana Valle, Cyril Quessada, Silvia Scaricamazza, Elisabetta Ferraro, Giacomo Giacovazzo, Gabriella Dobrowolny, Hao Wang, Valentina Nesci, Antonio Musarò, Niccolò Candelise, Cinzia Volonté, Illari Salvatori, Shyuan T. Ngo, Jean-Philippe Loeffler, Alberto Ferri, Frédérique René, Tesfaye Wolde Tefera, Susanna Amadio, Aniello Primiano, Andrea Urbani, Elisa Lepore, Alessio Torcinaro, Frederik J. Steyn, and Roberto Coccurello
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Pharmacology ,Hypermetabolism ,SOD1G93A mice ,Trimetazidine ,amyotrophic lateral sclerosis ,hypermetabolism ,mitochondria ,neurodegeneration ,business.industry ,Neurodegeneration ,Amyotrophic Lateral Sclerosis ,Skeletal muscle ,trimetazidine ,Motor neuron ,Spinal cord ,medicine.disease ,Mitochondria ,medicine.anatomical_structure ,medicine ,Amyotrophic lateral sclerosis ,business ,Neuroinflammation ,medicine.drug - Abstract
Background and purpose: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles is currently incurable despite intense research and numerous unsuccessful clinical trials. Although considered as a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single target drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug, trimetazidine, in SOD1G93A mice. Experimental approach: Trimetazidine is an anti-ischemic drug used for the treatment of coronary artery disease. As a metabolic modulator, Trimetazidine improves glucose metabolism. Furthermore, Trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. Here, we orally treated SOD1G93A mice with Trimetazidine, solubilized in drinking water at a dose of 20 mg/kg, from disease onset. We assessed the impact of Trimetazidine on disease progression by studying metabolic parameters, grip strength, and histological alterations in skeletal muscle, peripheral nerve and spinal cord. Key results: Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, Trimetazidine prevents the dismantlement of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. Conclusion and implications: In SOD1G93A mice, therapeutic effect of Trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord. Keywords: Amyotrophic Lateral Sclerosis; Hypermetabolism; Mitochondria; Neurodegeneration; SOD1G93A mice; Trimetazidine.
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- 2022
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15. Repurposing of Trimetazidine for amyotrophic lateral sclerosis: A study in SOD1
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Silvia, Scaricamazza, Illari, Salvatori, Susanna, Amadio, Valentina, Nesci, Alessio, Torcinaro, Giacomo, Giacovazzo, Aniello, Primiano, Michela, Gloriani, Niccolò, Candelise, Luisa, Pieroni, Jean-Philippe, Loeffler, Frederique, Renè, Cyril, Quessada, Tesfaye W, Tefera, Hao, Wang, Frederik J, Steyn, Shyuan T, Ngo, Gabriella, Dobrowolny, Elisa, Lepore, Andrea, Urbani, Antonio, Musarò, Cinzia, Volonté, Elisabetta, Ferraro, Roberto, Coccurello, Cristiana, Valle, and Alberto, Ferri
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Male ,Disease Models, Animal ,Mice ,Superoxide Dismutase-1 ,Superoxide Dismutase ,Amyotrophic Lateral Sclerosis ,Drug Repositioning ,Trimetazidine ,Animals ,Female ,Mice, Transgenic ,Neurodegenerative Diseases - Abstract
Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug used to treatment of coronary artery disease, trimetazidine, in SOD1As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. We orally treated SOD1Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1In SOD1
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- 2021
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