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A hallmark of these diseases is the pathological accumulation of \u03b1-synuclein aggregates, along with sustained neuroinflammatory responses. Recent studies have demonstrated the existence of structurally distinct \u03b1-synuclein aggregates in this group of the diseases. While the correlation between specific forms of \u03b1-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct \u03b1-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia, iMG) were treated with \u03b1-synuclein polymorphs including EGCG stabilized \u03b1-synuclein oligomers (EO), kinetically stable \u03b1-synuclein oligomers (KSO), dopamine stabilized \u03b1-synuclein oligomers (DO), \u03b1-synuclein preformed fibrils (PFF), sonicated \u03b1-synuclein preformed fibrils (sPFF), and matured \u03b1-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable \u03b1-synuclein oligomers and matured \u03b1-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct \u03b1-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable \u03b1-synuclein oligomers induce the activities of TLR2 and 4, and sonicated \u03b1-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct \u03b1-synuclein polymorphs have likewise distinct neuroinflammatory properties.<\/jats:p>","DOI":"10.1186\/s13041-025-01256-0","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T17:35:49Z","timestamp":1764956149000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Differential microglial responses to structurally distinct alpha-synuclein polymorphs"],"prefix":"10.1186","volume":"19","author":[{"given":"Katherine","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jina","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiyo","family":"Iba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyeon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandria","family":"Beilina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zulfeqhar A.","family":"Syed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Baena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Horan-Portelance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Cookson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungyong","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyoun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"1256_CR1","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1001\/archneur.58.2.186","volume":"58","author":"JE Galvin","year":"2001","unstructured":"Galvin JE, Lee VM, Trojanowski JQ. 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