@article{discovery10098982, year = {2020}, volume = {27}, title = {Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation}, note = {This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.}, publisher = {NATURE PUBLISHING GROUP}, month = {April}, pages = {2781--2796}, journal = {Cell Death \& Differentiation}, keywords = {Neural ageing, Neurological disorders}, author = {Angelova, PR and Choil, ML and Berezhnov, A and Horrocks, MH and Hughes, CD and De, S and Rodrigues, M and Yapom, R and Little, D and Dolt, KS and Kunath, T and Devine, MJ and Gissen, P and Shchepinov, MS and Sylantyev, S and Pavlov, E and Klenerman, D and Abramov, AY and Gandhi, S}, url = {https://doi.org/10.1038/s41418-020-0542-z}, 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 {\ensuremath{\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 {\ensuremath{\alpha}}-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. {\ensuremath{\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 {\ensuremath{\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.} }