Schwann cell-specific ablation of Beclin 1 impairs peripheral myelination and leads to a progressive motor and sensory neuropathy

Schwann cell-specific ablation of Beclin 1 impairs peripheral myelination and leads to a progressive motor and sensory neuropathy | 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 Schwann cell-specific ablation of Beclin 1 impairs peripheral myelination and leads to a progressive motor and sensory neuropathy Lisa Gambarotto, Silvia Bresolin, Luca Persano, Rachele D’Amore, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3596800/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The core component of the class III phosphatidylinositol 3-kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes and microglia, its role was far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot-Marie-Tooth diseases. By knocking out Beclin 1 in SCs we here generated a novel mouse model ( Becn1 cKO), developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10-day and 2-month-old mice revealed pro-mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. Our study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms. Biological sciences/Neuroscience/Glial biology/Schwann cell Health sciences/Neurology/Neurological disorders/Peripheral neuropathies Biological sciences/Cell biology/Autophagy/Macroautophagy Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryMaterials.pdf Supplementary Materials SupllementaryvideoBecn1cKO2mo.mov Supplementary video_Becn1cKO 2mo SupplementaryvideoBecn1cKO6mo.m4v Supplementary video_Becn1cKO 6mo SupplementaryvideoCTRL2mo.mov Supplementary video_CTRL 2mo Cite Share Download PDF Status: Posted 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3596800","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":248856776,"identity":"aa9c054b-74f3-46af-a4cd-68f1784d70c1","order_by":0,"name":"Lisa Gambarotto","email":"","orcid":"","institution":"University of Padova","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Gambarotto","suffix":""},{"id":248856777,"identity":"d60c7821-8920-49d0-a058-2f037a863ad5","order_by":1,"name":"Silvia Bresolin","email":"","orcid":"","institution":"University of 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While assessed in neurons, astrocytes and microglia, its role was far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot-Marie-Tooth diseases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBy knocking out Beclin 1 in SCs we here generated a novel mouse model (\u003cem\u003eBecn1\u003c/em\u003e cKO), developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. 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