Non-neuronal, TGF-β- extracellular matrix restructuring promotes neurodegeneration in a PSP-Richardson syndrome model

Zannino, C.; Valente, D.; Bressan, D.; Bruzelius, A.; Gabriele, C.; Scalise, S.; Covello, R.; Benedetto, G. L.; Talarico, M.; Abbonante, V.; Quattrone, A.; Gaspari, M.; Chiacchiera, F.; Fiorenzano, A.; Parrotta, E. I.; Cuda, G.

doi:10.1101/2025.08.17.670724

bioRxiv · 10.1101/2025.08.17.670724

Non-neuronal, TGF-β- extracellular matrix restructuring promotes neurodegeneration in a PSP-Richardson syndrome model

Zannino, C.·Valente, D.·Bressan, D.·Bruzelius, A.·Gabriele, C.·Scalise, S.·Covello, R.·Benedetto, G. L.·Talarico, M.·Abbonante, V.·Quattrone, A.·Gaspari, M.·Chiacchiera, F.·Fiorenzano, A.·Parrotta, E. I.·Cuda, G.

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Abstract

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a rapidly progressive tauopathy lacking effective therapies. Although tau aggregation is a defining feature, the initiating mechanisms remain elusive. Here we used patient-derived induced pluripotent stem cell midbrain organoids, integrating single-cell transcriptomics, bulk RNA profiling, and quantitative proteomics, to dissect early pathogenic events. We identified vascular leptomeningeal-like cells (VLMCs) as the first altered population, exhibiting TGF-{beta}-driven extracellular matrix (ECM) remodeling enriched in collagens, integrins, and TGFBI. The resulting pathological ECM increased stiffness, induced integrin clustering, and activated RhoA-ROCK-mediated cytoskeletal disorganization. These changes sustained PI3K-AKT and MAPK-ERK signaling, suppressed PP2A, hyperactivated mTOR, and impaired autophagy, culminating in tau hyperphosphorylation and mislocalization. Pharmacological inhibition of TGF-{beta}, AKT, ERK, or mTORC1 restored autophagic flux, reduced tau burden, and rescued neuronal architecture. Our findings establish non-neuronal, matrix-producing niche cells as upstream drivers of tauopathy and reveal TGF-{beta}-mediated ECM restructuring as a mechanochemical trigger of neurodegeneration, opening multiple therapeutic avenues for PSP-RS and related tauopathies.

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Zannino, C., Valente, D., Bressan, D., Bruzelius, A., Gabriele, C., Scalise, S., Covello, R., Benedetto, G. L., Talarico, M., Abbonante, V., Quattrone, A., Gaspari, M., Chiacchiera, F., Fiorenzano, A., Parrotta, E. I., Cuda, G.. 2025-08-18. Non-neuronal, TGF-β- extracellular matrix restructuring promotes neurodegeneration in a PSP-Richardson syndrome model. https://doi.org/10.1101/2025.08.17.670724

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