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