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Increasing evidence implicates \u03b1-syn-associated neuroinflammation as a contributor to PD pathogenesis, yet immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other synucleinopathies, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological \u03b1-syn or secondarily following neurodegeneration. We used the rat \u03b1-syn preformed fibril (PFF) model, in vitro complement assays and postmortem human PD tissue to investigate whether pathological \u03b1-syn directly activates complement prior to overt neurodegeneration. The \u03b1-syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak \u03b1-syn aggregation and nigrostriatal degeneration. Thus, we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy caused complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical (\n                    <jats:italic>C1qa, C1r, C4b<\/jats:italic>\n                    ) and alternative (\n                    <jats:italic>Cfd, Cfb<\/jats:italic>\n                    ) pathways, the anaphylatoxin (\n                    <jats:italic>C3aR, C5aR<\/jats:italic>\n                    ) and phagocytic (\n                    <jats:italic>CR3<\/jats:italic>\n                    ) complement receptors, and activation of complement C3. During early synucleinopathy microglia upregulated C3, which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulators, including Cd55, Cd59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1\u00a0protein were also observed in human postmortem PD SNc\u00a0tissue, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, \u03b1-syn directly binds C1q and activates the complement cascade in a C1q-dependent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03057-8","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T16:51:28Z","timestamp":1784566288000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complement dysregulation during the early phases of synucleinopathy"],"prefix":"10.1007","volume":"152","author":[{"given":"Hina","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Gifford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arash","family":"Kordbacheh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asher","family":"Bury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer","family":"Panoushek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson","family":"Cole-Strauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Kemp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin C.","family":"Luk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Steece-Collier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan C.","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Kanaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caryl E.","family":"Sortwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Patterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6801-7779","authenticated-orcid":false,"given":"Matthew J.","family":"Benskey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"3057_CR1","first-page":"3","volume":"120B","author":"KF Austen","year":"1979","unstructured":"Austen KF, Fearon DT (1979) A molecular basis of activation of the alternative pathway of human complement. 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NPJ Parkinsons Dis. https:\/\/doi.org\/10.1038\/s41531-025-01005-z","journal-title":"NPJ Parkinsons Dis"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-026-03057-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-026-03057-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-026-03057-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T16:51:30Z","timestamp":1784566290000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-026-03057-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":94,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3057"],"URL":"https:\/\/doi.org\/10.1007\/s00401-026-03057-8","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]},"assertion":[{"value":"30 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All postmortem human tissue used in the current study was de-identified. At no point was any of the tissue identified or linked to any identifying records of any kind. As such, this tissue is determined Not Human Subjects under the Michigan State University Study ID STUDY00009841. All procedures involving animals were performed in accordance with federal, state and institutional guidelines approved by the Michigan State University Institutional Animal Care and Use Committee (IACUC) under protocol number PROTO202400182.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"7"}}