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

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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 alpha-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 alpha-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. alpha-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 beta-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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2020-10
Language
English
Article Type
Article
Citation

CELL DEATH AND DIFFERENTIATION, v.27, no.10, pp.2781 - 2796

ISSN
1350-9047
DOI
10.1038/s41418-020-0542-z
URI
http://hdl.handle.net/10203/305023
Appears in Collection
BC-Journal Papers(저널논문)
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