Human serum-derived α-synuclein auto-antibodies mediate NMDA receptor-dependent degeneration of CNS neurons

2024 | journal article. A publication with affiliation to the University of Göttingen.

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​Human serum-derived α-synuclein auto-antibodies mediate NMDA receptor-dependent degeneration of CNS neurons​
Garg, P.; Würtz, F.; Hobbie, F.; Buttgereit, K.; Leite, K.; Aich, A. & Rehling, P. et al.​ (2024) 
Journal of Neuroinflammation21(1) art. 62​.​ DOI: https://doi.org/10.1186/s12974-024-03050-6 

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Authors
Garg, Pretty; Würtz, Franziska; Hobbie, Fabian; Buttgereit, Klemens; Leite, Kristian; Aich, Abhishek; Rehling, Peter; Kügler, Sebastian; Bähr, Mathias
Abstract
Abstract Background Presence of autoantibodies against α-synuclein (α-syn AAb) in serum of the general population has been widely reported. That such peripheral factors may be involved in central nervous system pathophysiology was demonstrated by detection of immunoglobulins (IgGs) in cerebrospinal fluid and brain of Parkinson’s disease (PD) patients. Thus, blood-borne IgGs may reach the brain parenchyma through an impaired blood-brain barrier (BBB). Findings The present study aims to evaluate the patho-physiological impact of α-syn AAbs on primary brain cells, i.e., on spontaneously active neurons and on astrocytes. Exposure of neuron-astrocyte co-cultures to human serum containing α-syn AAbs mediated a dose-dependent reduction of spontaneous neuronal activity, and subsequent neurodegeneration. Removal specifically of α-syn AAbs from the serum prevented neurotoxicity, while purified, commercial antibodies against α-syn mimicked the neurodegenerative effect. Mechanistically, we found a strong calcium flux into neurons preceding α-syn AAbs-induced cell death, specifically through NMDA receptors. NMDA receptor antagonists prevented neurodegeneration upon treatment with α-syn (auto)antibodies. α-syn (auto)antibodies did not affect astrocyte survival. However, in presence of α-syn, astrocytes reacted to α-syn antibodies by secretion of the chemokine RANTES. Conclusion These findings provide a novel basis to explain how a combination of BBB impairment and infiltration of IgGs targeting synuclein may contribute to neurodegeneration in PD and argue for caution with α-syn immunization therapies for treatment of PD.
Issue Date
2024
Journal
Journal of Neuroinflammation 
Project
EXC 2067: Multiscale Bioimaging 
Working Group
RG Bähr (Neurobiological Research Laboratory) 
External URL
https://mbexc.uni-goettingen.de/literature/publications/840
eISSN
1742-2094
Language
English

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