Motor System Oligodendroglia Atlas Reveals Activation States Associated with Region-Specific Vulnerability in ALS

Motor System Oligodendroglia Atlas Reveals Activation States Associated with Region-Specific Vulnerability in ALS | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Motor System Oligodendroglia Atlas Reveals Activation States Associated with Region-Specific Vulnerability in ALS Philip Van Damme, Maria Georgopoulou, Frederik Hobin, Jonas Dubin, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8351425/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Oligodendrocytes, the second most abundant cell type in the motor cortex and the most abundant in the spinal cord—are increasingly recognized as active contributors to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Yet their diversity and disease relevance in the central nervous system remain incompletely defined. Here, we generate a comprehensive single-nucleus transcriptomic atlas of 176 samples, integrating 2 in-house and 16 publicly available datasets. It encompasses more than 1,000,000 cells (350,000 oligodendrocytes and oligodendrocyte precursors) from the human motor cortex and spinal cord in non-neurological controls and ALS patients. We identify a previously unrecognized oligodendrocyte subpopulation—marked by PPEF1—and uncover regional differences, with distinct OPALIN+ and RBFOX1+ oligodendrocyte proportions between cortex and spinal cord. Importantly, we demonstrate that “disease-associated oligodendrocytes” (DAOs) represent a distinct activation state, rather than a distinct subpopulation. In ALS, spinal cord oligodendrocytes selectively shift toward reactive states, characterized by JUND-enriched regulon activity, heightened metabolic demand, increased intercellular signaling, and activation of cell-death pathways. Finally, we identify LRP2 as a novel transcriptional oligodendrocyte marker and find LRP2 and MBP proteins to be elevated in ALS cerebrospinal fluid (CSF), offering a potential biomarker of oligodendrocyte dysfunction. Our study provides a systems-level framework to interpret oligodendrocyte and OPC changes in ALS, linking cell state shifts to molecular alterations that can guide biomarker and therapeutic strategies. Biological sciences/Neuroscience/Diseases of the nervous system/Amyotrophic lateral sclerosis Biological sciences/Molecular biology/Transcriptomics Full Text Additional Declarations Yes there is potential Competing Interest. LVDB is head of the Scientific Advisory Board of Augustine Therapeutics (Leuven, Belgium) and is part of the Investment Advisory Board of Droia Ventures (Meise, Belgium). PVD has served in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, VectorY, Zambon, Amylyx, Novartis, Prilenia, Verge Genomics, Sapreme Technologies, Trace Neuroscience, NRG Therapeutics (paid to institution). PVD has received speaker fees from Biogen and Amylyx (paid to institution). PVD is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders (paid to institution). DRT received consultant honorary from Muna Therapeutics and collaborated with GE-Healthcare and Novartis. Supplementary Files Georgopoulouet.al.SupplementaryMaterial2025.xlsx Supplementary_Tables_S1_S22 Georgopoulouet.al.PreprintInfo2025.pdf Supplementary_Information_Preprint_bioRxiv Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Yet their diversity and disease relevance in the central nervous system remain incompletely defined. Here, we generate a comprehensive single-nucleus transcriptomic atlas of 176 samples, integrating 2 in-house and 16 publicly available datasets. It encompasses more than 1,000,000 cells (350,000 oligodendrocytes and oligodendrocyte precursors) from the human motor cortex and spinal cord in non-neurological controls and ALS patients. We identify a previously unrecognized oligodendrocyte subpopulation—marked by PPEF1—and uncover regional differences, with distinct OPALIN+ and RBFOX1+ oligodendrocyte proportions between cortex and spinal cord. Importantly, we demonstrate that “disease-associated oligodendrocytes” (DAOs) represent a distinct activation state, rather than a distinct subpopulation. In ALS, spinal cord oligodendrocytes selectively shift toward reactive states, characterized by JUND-enriched regulon activity, heightened metabolic demand, increased intercellular signaling, and activation of cell-death pathways. Finally, we identify LRP2 as a novel transcriptional oligodendrocyte marker and find LRP2 and MBP proteins to be elevated in ALS cerebrospinal fluid (CSF), offering a potential biomarker of oligodendrocyte dysfunction. 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