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Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

Published version
Peer-reviewed

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Authors

Angelova, Plamena R.  ORCID logo  https://orcid.org/0000-0003-4596-9117
Choi, Minee L. 
Berezhnov, Alexey V. 
Horrocks, Mathew H. 
Hughes, Craig D. 

Abstract

Abstract: Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson’s disease, and highlights a new mechanism by which lipid peroxidation causes cell death.

Description

Keywords

Article, /631/378/2611, /692/699/375, /14/19, /96/100, /96/2, article

Journal Title

Cell Death & Differentiation

Conference Name

Journal ISSN

1350-9047
1476-5403

Volume Title

27

Publisher

Nature Publishing Group UK
Sponsorship
Wellcome Trust (Wellcome) (WT089698)
Russian Foundation for Basic Research (RFBR) (20-34-70074)