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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,25]]},"abstract":"<jats:p>Alpha-Synuclein (\u03b1Syn) plays a central role in Parkinson\u2019s disease (PD), and the p.A53T mutation causes an early-onset familial form of PD with severe manifestations. While its effects on neurons are well studied, its consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated patient-derived p.A53T-\u03b1Syn induced pluripotent stem cells (iPSC) to ventral midbrain astrocytes and characterized them via comprehensive molecular, functional, and proteomic analyses. Gene-corrected and healthy iPSC-derived astrocytes served as controls. To assess the effects of p.A53T-\u03b1Syn astrocytes on dopamine neurons, we established neuron\u2013astrocyte cocultures of iPSC-derived control and mutant cells at all combinations. Our analyses uncovered cell-intrinsic pathologies in p.A53T-\u03b1Syn astrocytes, such as calcium dyshomeostasis, and accumulation of protein aggregates including those of phosphorylated \u03b1Syn. Proteomic and mechanistic studies demonstrated perturbed protein catabolic processes, with associated disturbances in lysosomal function and mTOR signaling. These deficits reduced the endocytic clearance capacity of p.A53T-\u03b1Syn astrocytes and their ability to process exogenous \u03b1Syn cargo. p.A53T-\u03b1Syn dopamine neurons cocultured with p.A53T-\u03b1Syn astrocytes displayed Lewy-like pathologies, mirroring the histopathological hallmarks identified in postmortem PD brains and exacerbated neurodegeneration, in anatomical and functional aspects. Control astrocytes mitigated these pathologies, highlighting their neuroprotective role. Additionally, p.A53T-\u03b1Syn astrocytes induced PD-relevant pathology \u03b9n control neurons. Our findings, validated using an isogenic pair, demonstrate a critical impact of p.A53T-\u03b1Syn in disrupting astrocytic protein quality control mechanisms and establish astrocytes as active contributors to PD neuropathology. Our two-dimensional coculture model reflects key aspects of PD pathology, offering a relevant platform for mechanistic and drug discovery studies.<\/jats:p>","DOI":"10.1073\/pnas.2505240122","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T20:00:32Z","timestamp":1763409632000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Dysregulated proteostasis in p.A53T-\u03b1-Synuclein astrocytes aggravates Lewy-like neuropathology in a Parkinson\u2019s disease iPSC model"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4944-7869","authenticated-orcid":false,"given":"Christina","family":"Paschou","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Hellenic Pasteur Institute","place":["Athens, Greece"]},{"name":"Human Embryonic and Induced Pluripotent Stem Cell Unit, Hellenic Pasteur 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induces apoptosis of astrocytes by causing dysfunction of the endoplasmic reticulum-Golgi compartment","volume":"18","author":"Liu M.","year":"2018","unstructured":"M. Liu , Alpha-Synuclein induces apoptosis of astrocytes by causing dysfunction of the endoplasmic reticulum-Golgi compartment. Mol. Med. Rep. 18, 322\u2013332 (2018).","journal-title":"Mol. Med. Rep."},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-023-00372-y"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1186\/1756-6606-3-12"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-023-02547-3"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1101738"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-012-8341-2"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-023-00363-z"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129462"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1520335113"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00621-8"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.109"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy147"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1704-z"},{"key":"e_1_3_5_66_2","unstructured":"M. Samiotaki F. Papastefanaki Data from \u201cProteostasis dysregulation in p.A53T-\u03b1-Synuclein iPSC-derived astrocytes exacerbates neurodegeneration in a Parkinson\u2019s disease model with Lewy-like pathology.\u201d PRIDE. https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD057491. Deposited 4 November 2024."}],"updated-by":[{"DOI":"10.1073\/pnas.2601834123","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2505240122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T18:49:48Z","timestamp":1770403788000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2505240122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":66,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2025,11,25]]}},"alternative-id":["10.1073\/pnas.2505240122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2505240122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]},"assertion":[{"value":"2025-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2505240122"}}