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Activation of the innate immune pathogen recognition receptor toll-like receptor 2 (TLR2) is associated with exacerbation of \u03b1-syn pathology. TLR2 is increased on neurons in the PD brain, and its activation results in the accumulation and propagation of \u03b1-syn through autophagy inhibition in neurons. In addition to the aggregation and propagation of pathological \u03b1-syn, dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD. However, the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address, given that TLR2 is a potential therapeutic target for PD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons (including DA neurons) and astrocytes. Cells were treated with or without the TLR2 agonist Pam3CSK4, and \u03b1-syn pathology was seeded using pre-formed fibrils. Confocal imaging was used to assess lysosomal function and \u03b1-syn pathology in the different cell types, as well as DA neuron health and astrocyte activation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>TLR2 activation acutely impaired the autophagy lysosomal pathway, and potentiated \u03b1-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes, leading to degeneration and loss of DA neurons. The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulated \u03b1-syn, and increases of A1 neurotoxic phenotypic proteins SerpinG1, complement C3, PSMB8 and GBP2. Moreover, the phenotypic changes in astrocytes correlated with a specific loss of DA neurons.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Taken together, these results support a role for astrocyte dysfunction in \u03b1-syn accumulation and DA neuronal loss following TLR2 activation in PD.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40035-024-00448-3","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T06:05:16Z","timestamp":1734329116000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Astrocytes contribute to toll-like receptor 2-mediated neurodegeneration and alpha-synuclein pathology in a human midbrain Parkinson\u2019s model"],"prefix":"10.1186","volume":"13","author":[{"given":"Fiona","family":"Weiss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Bardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenda M.","family":"Halliday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9121-0294","authenticated-orcid":false,"given":"Nicolas","family":"Dzamko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"issue":"2","key":"448_CR1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. 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