25 results on '"Schlachetzki, Johannes C."'
Search Results
2. Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain
- Author
-
Chung, Changuk, Yang, Xiaoxu, Hevner, Robert F., Kennedy, Katie, Vong, Keng Ioi, Liu, Yang, Patel, Arzoo, Nedunuri, Rahul, Barton, Scott T., Noel, Geoffroy, Barrows, Chelsea, Stanley, Valentina, Mittal, Swapnil, Breuss, Martin W., Schlachetzki, Johannes C. M., Kingsmore, Stephen F., and Gleeson, Joseph G.
- Published
- 2024
- Full Text
- View/download PDF
3. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia
- Author
-
Haney, Michael S., Pálovics, Róbert, Munson, Christy Nicole, Long, Chris, Johansson, Patrik K., Yip, Oscar, Dong, Wentao, Rawat, Eshaan, West, Elizabeth, Schlachetzki, Johannes C. M., Tsai, Andy, Guldner, Ian Hunter, Lamichhane, Bhawika S., Smith, Amanda, Schaum, Nicholas, Calcuttawala, Kruti, Shin, Andrew, Wang, Yung-Hua, Wang, Chengzhong, Koutsodendris, Nicole, Serrano, Geidy E., Beach, Thomas G., Reiman, Eric M., Glass, Christopher K., Abu-Remaileh, Monther, Enejder, Annika, Huang, Yadong, and Wyss-Coray, Tony
- Published
- 2024
- Full Text
- View/download PDF
4. Immune mechanisms of depression in rheumatoid arthritis
- Author
-
Brock, James, Basu, Neil, Schlachetzki, Johannes C. M., Schett, Georg, McInnes, Iain B., and Cavanagh, Jonathan
- Published
- 2023
- Full Text
- View/download PDF
5. Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management
- Author
-
Ellis, Ronald J., Marquine, María J., Kaul, Marcus, Fields, Jerel Adam, and Schlachetzki, Johannes C. M.
- Published
- 2023
- Full Text
- View/download PDF
6. Publisher Correction: Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management
- Author
-
Ellis, Ronald J., Marquine, María J., Kaul, Marcus, Fields, Jerel Adam, and Schlachetzki, Johannes C. M.
- Published
- 2023
- Full Text
- View/download PDF
7. Somatic mosaicism reveals clonal distributions of neocortical development
- Author
-
Breuss, Martin W., Yang, Xiaoxu, Schlachetzki, Johannes C. M., Antaki, Danny, Lana, Addison J., Xu, Xin, Chung, Changuk, Chai, Guoliang, Stanley, Valentina, Song, Qiong, Newmeyer, Traci F., Nguyen, An, O’Brien, Sydney, Hoeksema, Marten A., Cao, Beibei, Nott, Alexi, McEvoy-Venneri, Jennifer, Pasillas, Martina P., Barton, Scott T., Copeland, Brett R., Nahas, Shareef, Van Der Kraan, Lucitia, Ding, Yan, Glass, Christopher K., and Gleeson, Joseph G.
- Published
- 2022
- Full Text
- View/download PDF
8. Genomic Mosaicism of the Brain: Origin, Impact, and Utility
- Author
-
Graham, Jared H., primary, Schlachetzki, Johannes C. M., additional, Yang, Xiaoxu, additional, and Breuss, Martin W., additional
- Published
- 2023
- Full Text
- View/download PDF
9. CSF1R-Mediated Myeloid Cell Depletion Prolongs Lifespan But Aggravates Distinct Motor Symptoms in a Model of Multiple System Atrophy
- Author
-
Battis, Kristina, primary, Florio, Jazmin B., additional, Mante, Michael, additional, Lana, Addison, additional, Naumann, Isabel, additional, Gauer, Carina, additional, Lambrecht, Vera, additional, Müller, Simon Julian, additional, Cobo, Isidoro, additional, Fixsen, Bethany, additional, Kim, Ha Yeon, additional, Masliah, Eliezer, additional, Glass, Christopher K., additional, Schlachetzki, Johannes C. M., additional, Rissman, Robert A., additional, Winkler, Jürgen, additional, and Hoffmann, Alana, additional
- Published
- 2022
- Full Text
- View/download PDF
10. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
- Author
-
Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS
- Subjects
Adult ,Male ,TDP-43 ,C9orf72 ,SLITRK2 ,amyotrophic lateral sclerosis ,frontotemporal dementia ,Nerve Tissue Proteins ,Settore MED/03 - GENETICA MEDICA ,Polymorphism, Single Nucleotide ,Cohort Studies ,Genes, X-Linked ,80 and over ,Medicine ,Dementia ,Humans ,Allele ,Age of Onset ,Polymorphism ,Aged ,Aged, 80 and over ,biology ,C9orf72 Protein ,business.industry ,Membrane Proteins ,MESH: Frontotemporal Lobar Degeneration / epidemiology ,Frontotemporal Lobar ,Degeneration / genetics ,Genes, X-Linked / genetics ,Genome-Wide Association Study / methods ,Frontotemporal lobar degeneration ,Single Nucleotide ,Middle Aged ,X-Linked ,medicine.disease ,Amyotrophic lateral sclerosis ,Minor allele frequency ,Genes ,Immunology ,Synaptophysin ,biology.protein ,Female ,MESH: Adult ,C9orf72 Protein / genetics ,Frontotemporal Lobar Degeneration / diagnosis ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Human medicine ,Neurology (clinical) ,MESH: Humans ,Membrane Proteins / genetics ,Nerve Tissue Proteins / genetics ,Polymorphism, Single Nucleotide / genetics ,Age of onset ,Frontotemporal Lobar Degeneration ,business ,Frontotemporal dementia ,Genome-Wide Association Study - Abstract
The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
- Published
- 2021
11. A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.
- Author
-
Abdel-Haq, Reem, Schlachetzki, Johannes C. M., Boktor, Joseph C., Cantu-Jungles, Thaisa M., Thron, Taren, Mengying Zhang, Bostick, John W., Khazaei, Tahmineh, Chilakala, Sujatha, Morais, Livia H., Humphrey, Greg, Keshavarzian, Ali, Katz, Jonathan E., Thomson, Matthew, Knight, Rob, Gradinaru, Viviana, Hamaker, Bruce R., Glass, Christopher K., and Mazmanian, Sarkis K.
- Subjects
- *
PREBIOTICS , *ALPHA-synuclein , *HIGH-fiber diet , *MICROGLIA , *SHORT-chain fatty acids , *GENETIC overexpression - Abstract
Parkinson’s disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
12. Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes.
- Author
-
Franco-Enzástiga Ú, Inturi NN, Natarajan K, Mwirigi JM, Mazhar K, Schlachetzki JCM, Schumacher M, and Price TJ
- Abstract
Gene expression is influenced by chromatin architecture via controlled access of regulatory factors to DNA. To better understand gene regulation in the human dorsal root ganglion (hDRG) we used bulk and spatial transposase-accessible chromatin technology followed by sequencing (ATAC-seq). Using bulk ATAC-seq, we detected that in females diverse differentially accessible chromatin regions (DARs) mapped to the X chromosome and in males to autosomal genes. EGR1/3 and SP1/4 transcription factor binding motifs were abundant within DARs in females, and JUN, FOS and other AP-1 factors in males. To dissect the open chromatin profile in hDRG neurons, we used spatial ATAC-seq. The neuron cluster showed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in females, and in Ca
2+ - signaling-related genes in males. Sex differences in transcription factor binding sites in neuron-proximal barcodes were consistent with the trends observed in bulk ATAC-seq data. We validated that EGR1 expression is biased to female hDRG compared to male. Strikingly, XIST , the long-noncoding RNA responsible for X inactivation, hybridization signal was found to be highly dispersed in the female neuronal but not non-neuronal nuclei suggesting weak X inactivation in female hDRG neurons. Our findings point to baseline epigenomic sex differences in the hDRG that likely underlie divergent transcriptional responses that determine mechanistic sex differences in pain., Competing Interests: Conflict of Interest Statement The authors declare no financial conflicts of interest related to this work.- Published
- 2024
- Full Text
- View/download PDF
13. Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV.
- Author
-
Matt SM, Nolan R, Manikandan S, Agarwal Y, Channer B, Oteju O, Daniali M, Canagarajah JA, LuPone T, Mompho K, Runner K, Nickoloff-Bybel E, Li B, Niu M, Schlachetzki JCM, Fox HS, and Gaskill PJ
- Abstract
The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.
- Published
- 2024
- Full Text
- View/download PDF
14. Cell-type-resolved somatic mosaicism reveals clonal dynamics of the human forebrain.
- Author
-
Chung C, Yang X, Hevner RF, Kennedy K, Vong KI, Liu Y, Patel A, Nedunuri R, Barton ST, Barrows C, Stanley V, Mittal S, Breuss MW, Schlachetzki JCM, and Gleeson JG
- Abstract
Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the structural organization and cellular origins. Here, we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific Mosaic Variant Barcode Analysis. From four hemispheres from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1
+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus cell-type resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain., Competing Interests: Competing interests K.K. is a senior scientist at Bioskryb Genomics Inc. All other authors declare no competing interests.- Published
- 2023
- Full Text
- View/download PDF
15. RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression.
- Author
-
Abe Y, Kofman ER, Almeida M, Ouyang Z, Ponte F, Mueller JR, Cruz-Becerra G, Sakai M, Prohaska TA, Spann NJ, Resende-Coelho A, Seidman JS, Stender JD, Taylor H, Fan W, Link VM, Cobo I, Schlachetzki JCM, Hamakubo T, Jepsen K, Sakai J, Downes M, Evans RM, Yeo GW, Kadonaga JT, Manolagas SC, Rosenfeld MG, and Glass CK
- Subjects
- Humans, Mice, Animals, Co-Repressor Proteins genetics, RANK Ligand genetics, Nuclear Receptor Co-Repressor 1 genetics, Nuclear Receptor Co-Repressor 1 metabolism, Gene Expression, RNA, Osteoclasts metabolism
- Abstract
The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts., Competing Interests: Declaration of interests C.K.G. is a co-founder, equity holder, and member of the Scientific Advisory Board of Asteroid Therapeutics. J.T.K. is on the Molecular Cell advisory board., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
16. Human microglia maturation is underpinned by specific gene regulatory networks.
- Author
-
Han CZ, Li RZ, Hansen E, Trescott S, Fixsen BR, Nguyen CT, Mora CM, Spann NJ, Bennett HR, Poirion O, Buchanan J, Warden AS, Xia B, Schlachetzki JCM, Pasillas MP, Preissl S, Wang A, O'Connor C, Shriram S, Kim R, Schafer D, Ramirez G, Challacombe J, Anavim SA, Johnson A, Gupta M, Glass IA, Levy ML, Haim SB, Gonda DD, Laurent L, Hughes JF, Page DC, Blurton-Jones M, Glass CK, and Coufal NG
- Subjects
- Humans, Mice, Animals, Gene Regulatory Networks, Brain, Gene Expression Regulation, Microglia, Induced Pluripotent Stem Cells
- Abstract
Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes., Competing Interests: Declaration of interests M.B.-J. is a co-inventor of patent application WO/2018/160496, related to the differentiation of pluripotent stem cells into microglia and co-founder of NovoGlia, Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
17. Correction: A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.
- Author
-
Abdel-Haq R, Schlachetzki JCM, Boktor JC, Cantu-Jungles TM, Thron T, Zhang M, Bostick JW, Khazaei T, Chilakala S, Morais LH, Humphrey G, Keshavarzian A, Katz JE, Thomson M, Knight R, Gradinaru V, Hamaker BR, Glass CK, and Mazmanian SK
- Published
- 2023
- Full Text
- View/download PDF
18. An in vivo neuroimmune organoid model to study human microglia phenotypes.
- Author
-
Schafer ST, Mansour AA, Schlachetzki JCM, Pena M, Ghassemzadeh S, Mitchell L, Mar A, Quang D, Stumpf S, Ortiz IS, Lana AJ, Baek C, Zaghal R, Glass CK, Nimmerjahn A, and Gage FH
- Subjects
- Humans, Brain, Macrophages, Phenotype, Microglia, Organoids
- Abstract
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
19. Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice.
- Author
-
Han RT, Vainchtein ID, Schlachetzki JCM, Cho FS, Dorman LC, Ahn E, Kim DK, Barron JJ, Nakao-Inoue H, Molofsky AB, Glass CK, Paz JT, and Molofsky AV
- Subjects
- Animals, Mice, Synapses metabolism, Brain metabolism, Seizures metabolism, Mice, Inbred C57BL, Microglia metabolism, Interleukin-33 metabolism
- Abstract
Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement., (© 2022 Han et al.)
- Published
- 2023
- Full Text
- View/download PDF
20. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4.
- Author
-
Gratuze M, Schlachetzki JCM, D'Oliveira Albanus R, Jain N, Novotny B, Brase L, Rodriguez L, Mansel C, Kipnis M, O'Brien S, Pasillas MP, Lee C, Manis M, Colonna M, Harari O, Glass CK, Ulrich JD, and Holtzman DM
- Subjects
- Mice, Animals, Inflammation metabolism, Microglia metabolism, Disease Models, Animal, Membrane Glycoproteins metabolism, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Alzheimer Disease metabolism
- Abstract
In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4., Competing Interests: Declaration of interests D.M.H. is as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. and J.D.U. are inventors on a submitted patent on TREM2 antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech (South San Francisco, CA), and Cajal Neuroscience and consults for Alector. D.M.H. is on the advisory board for Neuron., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
21. Human microglia phenotypes in the brain associated with HIV infection.
- Author
-
Schlachetzki JCM, Zhou Y, and Glass CK
- Subjects
- Humans, Microglia, Brain, Phenotype, HIV Infections complications
- Abstract
Cognitive impairment in individuals infected with HIV is highly prevalent despite life-long antiretroviral therapy. A growing line of evidence suggests that the human brain serves as a sanctuary for HIV persistence. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for HIV and drive the pathogenesis of HIV-associated neurocognitive disorders. Here, we highlight recent advances in understanding microglia diversity in HIV regarding their epigenome, transcriptome, and function., Competing Interests: Conflict of interest statement Noe declared., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
22. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease.
- Author
-
Herdy JR, Traxler L, Agarwal RK, Karbacher L, Schlachetzki JCM, Boehnke L, Zangwill D, Galasko D, Glass CK, Mertens J, and Gage FH
- Subjects
- Humans, Aged, Neurons, Astrocytes, Oncogenes, Brain, Alzheimer Disease
- Abstract
The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and increased risk of age-related disease. We found that Alzheimer's disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD., Competing Interests: Declaration of interests F.H.G. is an advisory board member of Cell Stem Cell., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
23. Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease.
- Author
-
Traxler L, Herdy JR, Stefanoni D, Eichhorner S, Pelucchi S, Szücs A, Santagostino A, Kim Y, Agarwal RK, Schlachetzki JCM, Glass CK, Lagerwall J, Galasko D, Gage FH, D'Alessandro A, and Mertens J
- Subjects
- Glycolysis, Humans, Protein Isoforms genetics, Protein Isoforms metabolism, Pyruvate Kinase genetics, Pyruvate Kinase metabolism, Alzheimer Disease, Neoplasms pathology
- Abstract
The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching of the glycolytic enzyme pyruvate kinase M (PKM) toward the cancer-associated PKM2 isoform conferred metabolic and transcriptional changes in AD iNs. These alterations occurred via PKM2's lack of metabolic activity and via nuclear translocation and association with STAT3 and HIF1α to promote neuronal fate loss and vulnerability. Chemical modulation of PKM2 prevented nuclear translocation, restored a mature neuronal metabolism, reversed AD-specific gene expression changes, and re-activated neuronal resilience against cell death., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
24. Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer's patients.
- Author
-
Mertens J, Herdy JR, Traxler L, Schafer ST, Schlachetzki JCM, Böhnke L, Reid DA, Lee H, Zangwill D, Fernandes DP, Agarwal RK, Lucciola R, Zhou-Yang L, Karbacher L, Edenhofer F, Stern S, Horvath S, Paquola ACM, Glass CK, Yuan SH, Ku M, Szücs A, Goldstein LSB, Galasko D, and Gage FH
- Subjects
- Aged, Aging, Fibroblasts, Humans, Neurons, Alzheimer Disease, Induced Pluripotent Stem Cells
- Abstract
Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity., Competing Interests: Declaration of interests F.H.G. is an advisory board member of Cell Stem Cell., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
25. Chronic peripheral inflammation: a possible contributor to neurodegenerative diseases.
- Author
-
Süβ P, Lana AJ, and Schlachetzki JCM
- Abstract
The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is an outstanding question. Sustained activation of the peripheral innate and adaptive immune systems occurs in the context of a broad array of disorders ranging from chronic infectious diseases to autoimmune and metabolic diseases. In addition, progressive systemic inflammation is increasingly recognized during aging. Peripheral immune cells could potentially modulate the cellular brain environment via the secretion of soluble molecules. There is an ongoing debate whether peripheral immune cells have the potential to migrate into the brain under certain permissive circumstances. In this perspective, we discuss the possible contribution of chronic peripheral inflammation to the pathogenesis of age-related neurodegenerative diseases with a focus on microglia, the resident immune cells of the brain parenchyma., Competing Interests: None
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.