{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T18:08:09Z","timestamp":1792260489066,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP\u2010Richardson's syndrome (PSP\u2010RS) using multi\u2010donor midbrain organoids (MOs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP\u2010RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120\u2009days to assess neuronal death, reactive gliosis, and the accumulation of 4R\u2010tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202\/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PSP\u2010derived MOs showed progressive size reduction compared with HC\u2010derived MOs, linked to upregulated apoptosis\u2010related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90\u2009days, along with a significant rise in GFAP\u2010positive cells in PSP\u2010derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted\u2010shaped astrocytes, absent in HC\u2010derived organoids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. 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