Extracellular matrix remodeling links vascular–stromal dysfunction to neuronal tau pathology in Progressive Supranuclear Palsy

Extracellular matrix remodeling links vascular–stromal dysfunction to neuronal tau pathology in Progressive Supranuclear Palsy | 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 Extracellular matrix remodeling links vascular–stromal dysfunction to neuronal tau pathology in Progressive Supranuclear Palsy Elvira Parrotta, Clara Zannino, Desirèe Valente, Davide Bressan, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7956425/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 Progressive supranuclear palsy-Richardson’s syndrome (PSP-RS) is a primary tauopathy lacking disease-modifying treatments, and the pathogenic mechanisms remain poorly understood. Here, combining patient-derived midbrain organoids with single-cell and bulk transcriptomics, quantitative proteomics, and functional assays, we identified extracellular matrix (ECM) dysregulation as an early pathogenic event. Vascular leptomeningeal-like cells (VLMCs) – a perivascular cell type recognized as a key component of the human dopaminergic lineage specification – emerged as dominant contributors, exhibiting excessive collagen deposition and upregulation of latent TGF-β-binding proteins. This fibrotic remodeling generated a stiff, adhesive microenvironment that mechanically retained and primed latent TGF-βs complexes for activation. Mechanical cues facilitated TGF-β release, triggering AKT-mTORC1 and RhoA/ROCK signaling pathways that converged on defective proteostasis, tau hyperphosphorylation and mislocalization, and synaptic degeneration. Pharmacological inhibition of ALK5/TGFBR1 restored cytoskeletal stability, autophagic flux, tau homeostasis, and neuronal morphology. Together, these findings identify ECM mechanotransduction, largely orchestrated by VLMC-derived components, as an upstream determinant of neuronal degeneration in PSP-RS and establish the ECM-TGF-β axis as a promising therapeutic target. Biological sciences/Neuroscience/Molecular neuroscience Health sciences/Diseases/Neurological disorders/Neurodegeneration Biological sciences/Cell biology/Cytoskeleton/Actin Biological sciences/Cell biology/Cell signalling/Extracellular signalling molecules Progressive supranuclear palsy-Richardson syndrome (PSP-RS) tauopathy extracellular matrix (ECM) vascular leptomeningeal-like cells (VLMCs) TGF-β cytoskeleton synaptic vulnerability scRNA-seq transcriptomics proteomics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementaryinformation.pdf Primers and antibodies 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-7956425","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":536551611,"identity":"ecc75ac1-4338-49b8-a102-4e057ae8585a","order_by":0,"name":"Elvira 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