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Open Access 01-12-2024 | Research

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

Authors: Pretty Garg, Franziska Würtz, Fabian Hobbie, Klemens Buttgereit, Abhishek Aich, Kristian Leite, Peter Rehling, Sebastian Kügler, Mathias Bähr

Published in: Journal of Neuroinflammation | Issue 1/2024

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.

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Title: Human serum-derived α-synuclein auto-antibodies mediate NMDA receptor-dependent degeneration of CNS neurons
Authors: Pretty Garg
Franziska Würtz
Fabian Hobbie
Klemens Buttgereit
Abhishek Aich
Kristian Leite
Peter Rehling
Sebastian Kügler
Mathias Bähr
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-024-03050-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Findings

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Findings

Conclusion

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