{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:35:18Z","timestamp":1785429318200,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,11]]},"group-title":"Neuroscience","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/0472cxd90","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01frxsf98","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03fsqvg68","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant\n                  <jats:italic>SOD1<\/jats:italic>\n                  expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of \u2018myelinic nanochannels\u2019, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Oligodendrocytes have been implicated in the progression of amyotrophic lateral sclerosis (ALS) but the underlying mechanisms have remained obscure. Here we show in genetic mouse models that the familial ALS causing isoform of a ubiquitously expressed mutant enzyme (SOD1) aggregates in cytosolic channels within myelin that are responsible for delivery of transporters and nutrients necessary to support the axonal compartment. ALS disease progression was accelerated in mice when myelinic channels were collapsed by deleting CNP, a structural protein necessary for myelinic channel maintenance. Disruption of transport through myelinic channels by aggregation of mutant SOD1 may perturb oligodendrocyte support of motor axons and contribute to disease in this form of ALS.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.09.731100","type":"posted-content","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:30:23Z","timestamp":1781224223000},"source":"Crossref","is-referenced-by-count":0,"title":["Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3180-6405","authenticated-orcid":false,"given":"Alexandra I.","family":"Mot","sequence":"first","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3885-5201","authenticated-orcid":false,"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1585-6330","authenticated-orcid":false,"given":"Payam","family":"Dibaj","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"name":"Center for Rare Diseases G\u00f6ttingen, Department of Pediatrics and Pediatric Neurology, Georg August University G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1206-6202","authenticated-orcid":false,"given":"Iva D.","family":"Tzvetanova","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"name":"Section of Pharmacology, School of Medicine, European University Cyprus, Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike C.","family":"Gerwig","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0905-2654","authenticated-orcid":false,"given":"Tizibt A.","family":"Bogale","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"name":"School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8343-9972","authenticated-orcid":false,"given":"Sandra","family":"Goebbels","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-7165","authenticated-orcid":false,"given":"Wiebke","family":"M\u00f6bius","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"name":"Electron Microscopy Unit, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7133-7378","authenticated-orcid":false,"given":"Dwight E.","family":"Bergles","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"name":"Kavli Neuroscience Discovery Institute, Johns Hopkins University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-3899","authenticated-orcid":false,"given":"Brett M.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2001-8470","authenticated-orcid":false,"given":"Jeffrey D.","family":"Rothstein","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, 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