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

Plamena R Angelova, Minee L. Choi, Alexey V Berezhnov, Mathew Horrocks, Craig D. Hughes, Suman De, Margarida Rodrigues, Ratsuda Yapom, Daniel Little, Karamjit Dolt, Tilo Kunath, Michael J Devine, Paul Gissen, Mikhail S. Shchepinov, Sergiy Sylantyev, Evgeny V Pavlov, David Klenerman, Andrey Y Abramov, Sonia Gandhi

Research output: Contribution to journalArticlepeer-review

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, characterised 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 signalling due 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 signalling. 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 languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusPublished - 27 Apr 2020

Keywords

  • alpha-synuclein
  • calcium signalling
  • synucleinopathy
  • Parkinson's disease
  • ferroptosis
  • iPSC--derived neurons
  • electrophysiology

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