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bioRxiv · 10.1101/2025.11.18.687143

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

Hennegan, J.·Teeling, J.·Roghanian, A.·Cragg, M.·Duriez, P.·Cox, K.·Oldham, R.·Douglas, L.·Frendeus, B.·Hurley, M.
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Abstract

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.

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Hennegan, J., Teeling, J., Roghanian, A., Cragg, M., Duriez, P., Cox, K., Oldham, R., Douglas, L., Frendeus, B., Hurley, M.. 2025-11-18. Deletion or Targeted Blockade of FcγRIIb (CD32b) Impairs α-Syn Propagation In-Vivo. https://doi.org/10.1101/2025.11.18.687143

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