Deletion or immunotherapeutic blockade of FcγRIIb (CD32b) impairs α-Syn propagation in vivo.

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Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterised by widespread alpha-synuclein (α-Syn) pathology in the brain and the progressive degeneration of nigrostriatal dopaminergic neurons. Experimental and clinicopathological data support a templated, prion-like component to α-Syn spread; however, the cellular mechanisms governing fibril uptake and intercellular transmission remain incompletely defined. Fc gamma receptor IIb (FcγRIIb or CD32b), the sole cross-species inhibitory Fcγ receptor, has been implicated in α-Syn internalisation in vitro, though its contribution to α-Syn propagation in vivo is not well established. Here, we examine the role of FcγRIIb in α-Syn seeding, propagation, and neurotoxicity in vivo using the preformed fibril (PFF) α-Syn intracranial injection model in mice. Genetic ablation of murine FcγRII reduced phosphorylated α-Syn (pα-Syn) burden and anatomical distribution across multiple brain regions at 90 days post-PFF injection, consistent with impaired development of Lewy-like pathology. Attenuated pα-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) FcγRIIb using monoclonal antibodies reduced acute-phase pα-Syn accumulation in hFcγRIIb-transgenic mice following PFF challenge. Collectively, these findings identify FcγRIIb as a critical regulator of α-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 α-synucleinopathies.

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