Deletion or Targeted Blockade of FcγRIIb (CD32b) Impairs α-Syn Propagation <i>In-Vivo</i>

Abstract Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is characterised by pervasive deposition of alpha-synuclein (α-Syn) aggregates and the death of dopaminergic neurons. Fc gamma receptor IIb (FcγRIIb or CD32b), the sole inhibitory FcγR in humans (h) and mice (m), serves as a molecular conduit for intercellular α-Syn transmission in-vitro . Here, we demonstrate that FcγRIIb facilitates α-Syn propagation and neurotoxicity in-vivo using the pre-formed fibril (PFF) α-Syn model in mice. Genetic ablation of mFcγRII attenuated PFF α-Syn-induced Lewy pathology, dampened associated neuroinflammatory responses, and preserved nigrostriatal dopaminergic neurons. Furthermore, pharmacological blockade of hFcγRIIb using clinically-related monoclonal antibodies mitigated acute-phase α-Syn pathology in hFcγRIIb-transgenic mice following PFF challenge. Collectively, our results indicate that FcγRIIb is a mediator of α-Syn propagation in-vivo and highlight it as a tractable therapeutic target against α-synucleinopathies like PD.