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Experimental and clinicopathological data support a templated, prion-like component to \u03b1-Syn spread; however, the cellular mechanisms governing fibril uptake and intercellular transmission remain incompletely defined. Fc gamma receptor IIb (Fc\u03b3RIIb or CD32b), the sole cross-species inhibitory Fc\u03b3 receptor, has been implicated in \u03b1-Syn internalisation in vitro, though its contribution to \u03b1-Syn propagation in vivo is not well established. Here, we examine the role of Fc\u03b3RIIb in \u03b1-Syn seeding, propagation, and neurotoxicity in vivo using the preformed fibril (PFF) \u03b1-Syn intracranial injection model in mice. Genetic ablation of murine Fc\u03b3RII reduced phosphorylated \u03b1-Syn (p\u03b1-Syn) burden and anatomical distribution across multiple brain regions at 90\u00a0days post-PFF injection, consistent with impaired development of Lewy-like pathology. Attenuated p\u03b1-Syn pathology was accompanied by reduced microglial reactivity, preservation of nigrostriatal dopaminergic integrity, and protection from PFF-associated motor and exploratory deficits. In parallel, pharmacological blockade of human (h) Fc\u03b3RIIb using monoclonal antibodies reduced acute-phase p\u03b1-Syn accumulation in hFc\u03b3RIIb-transgenic mice following PFF challenge. Collectively, these findings identify Fc\u03b3RIIb as a critical regulator of \u03b1-Syn propagation in vivo and support receptor-targeted blockade as a mechanistically distinct and therapeutically tractable strategy for modifying disease progression in PD and related \u03b1-synucleinopathies.<\/jats:p>","DOI":"10.1007\/s00401-026-03082-7","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:37:19Z","timestamp":1790336239000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deletion or immunotherapeutic blockade of Fc\u03b3RIIb (CD32b) impairs \u03b1-Syn propagation in vivo"],"prefix":"10.1007","volume":"152","author":[{"given":"James M.","family":"Hennegan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Hurley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Colley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry L.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon R.","family":"Douglas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Duriez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Oldham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Cragg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Frend\u00e9us","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Roghanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Teeling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"3082_CR1","unstructured":"(2021) BI-1206 and an Anti-CD20 Antibody in Patients With CD32b Positive B-cell Lymphoma or Leukaemia https:\/\/clinicaltrials.gov\/study\/NCT02933320. 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