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

Overview

1. Experimental NeuroImmunology, School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD UK
2. Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD UK
3. Parkinson’s UK, London, UK
4. Present Address: Curve Therapeutics, Southampton Science Park, Southampton, SO16 7NS UK
5. Institute for Life Sciences, University of Southampton, Highfield, Southampton, UK
6. BioInvent International AB, Solvegatan 41, 22370 Lund, Sweden

Abstract

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.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00401-026-03082-7.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• uniprot.org/align, at UniProt; found in the text, “Discussion”

Data availability

The data supporting the findings of this study are available from the corresponding author upon request. All data were generated and analysed during the current study. A version of this manuscript (preprint) is available in the public domain in the BioRxiv (BioArchive) repository (https://doi.org/10.1101/2025.11.18.687143v1).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: n/a → Springer Science+Business Media
• Funding: added Gerald Kerkut Charitable Trust; University of Southampton; Wessex Medical Research

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 6 keywords, 14 MeSH terms, 42 references.

Cite

This paper

Hennegan, J. M., Hurley, M. J., Colley, M., Cox, K. L., Douglas, L. R., Duriez, P. J., Oldham, R. J., Cragg, M. S., Frendéus, B., Roghanian, A., & Teeling, J. L. (2026). Deletion or immunotherapeutic blockade of FcγRIIb (CD32b) impairs α-Syn propagation in vivo. Acta neuropathologica, 152(1), 40. https://doi.org/10.1007/s00401-026-03082-7

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