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

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.