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.
Original language | English |
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Pages (from-to) | 2781-2796 |
Number of pages | 16 |
Journal | Cell Death and Differentiation |
Volume | 27 |
Issue number | 10 |
Early online date | 27 Apr 2020 |
DOIs | |
Publication status | Published - Oct 2020 |
Bibliographical note
Correction to: Cell Death & Differentiationhttps://doi.org/10.1038/s41418-020-0542-z
This article was originally published under a non-CC-BY licence, but has now been made available under a CC-BY 4.0 license.
The PDF and HTML versions of the paper have been modified accordingly.
Correction to: Cell Death & Differentiation
https://doi.org/10.1038/s41418-020-0542-z
The Affiliation ‘UCL Queen Square Institute of Neurology’ appeared incorrectly in the original article as ‘UCL Institute of Neurology’
This has been corrected in the PDF and HTML versions.
Acknowledgements
This work was supported by the Wellcome/MRC Parkinson’s Disease Consortium grant (grant number WT089698), the Leverhulme Trust and the National Institute of Health Research University College London Hospitals Biomedical Research Centre. S.G. was supported by Wellcome, and is an MRC Senior Clinical Fellow. KSD and TK were supported by a Parkinson’s UK Senior Fellowship (ref. F-0902). RY and TK were supported by MRC grant MR/J012831/1. The study was funded additionally by RFBR, project number 20-34-70074. M. Schepinov is employed by Retrotope Inc. This work was supported by the grant of the Russian Federation Government no. 075-15-2019-1877.
Keywords
- REGULATED CELL-DEATH
- PARKINSONS-DISEASE
- LEWY BODIES
- CA2+ INFLUX
- OLIGOMERS
- ASSOCIATION
- ASTROCYTES
- MUTATION
- FORMS
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