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Here, we generated induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons from individuals with sporadic PSP-RS and matched healthy controls and performed integrated transcriptomic and proteomic analyses. PSP-RS neurons exhibited coordinated suppression of dopaminergic and synaptic programs alongside activation of cytoskeletal remodeling and stress-related pathways. These changes were accompanied by increased Tau phosphorylation, neurofilament accumulation, and structural alterations of the axonal compartment, consistent with an early axonopathic phenotype. Notably, mechanistic target of rapamycin (mTOR) signaling significantly increased. Pharmacological inhibition of mTOR reduced Tau phosphorylation and neurofilament levels, indicating that mTOR activity contributes to the maintenance of cytoskeletal imbalance. In conclusion, our findings support a model in which early cytoskeletal dysfunction in PSP-RS arises from the convergence of Tau dysregulation, impaired structural homeostasis, and altered signaling pathways. Rather than acting as a primary driver, mTOR appears to function as a pathogenic amplifier that sustains axonal stress. This study provides a human cellular framework to investigate early axonopathic mechanisms in sporadic PSP-RS.<\/jats:p>","DOI":"10.3390\/cells15090754","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:04:42Z","timestamp":1776945882000},"page":"754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytoskeletal Imbalance and Axonal Vulnerability in Sporadic PSP-RS: Early Changes in a Human iPSC-Derived Neuronal Model with Altered mTOR Signaling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2571-2879","authenticated-orcid":false,"given":"Raffaele","family":"Covello","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8585-2144","authenticated-orcid":false,"given":"Giorgia Lucia","family":"Benedetto","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6979-1486","authenticated-orcid":false,"given":"Stefania","family":"Scalise","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2584-1335","authenticated-orcid":false,"given":"Caterina","family":"Gabriele","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e8e","family":"Valente","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Zannino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Science, Lund University, 22100 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1189-3628","authenticated-orcid":false,"given":"Barbara","family":"Puccio","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2071-2083","authenticated-orcid":false,"given":"Andrea","family":"Quattrone","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"},{"name":"Neuroscience Research Center, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-2997","authenticated-orcid":false,"given":"Pietro Hiram","family":"Guzzi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5411-8800","authenticated-orcid":false,"given":"Marco","family":"Gaspari","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Quattrone","sequence":"additional","affiliation":[{"name":"Neuroscience Research Center, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-1866","authenticated-orcid":false,"given":"Giovanni","family":"Cuda","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8145-3623","authenticated-orcid":false,"given":"Elvira Immacolata","family":"Parrotta","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1001\/archneur.1964.00460160003001","article-title":"Progressive Supranuclear Palsy. 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