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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

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 languageEnglish
Pages (from-to)2781-2796
Number of pages16
JournalCell Death and Differentiation
Volume27
Issue number10
Early online date27 Apr 2020
DOIs
Publication statusPublished - Oct 2020

Keywords

  • REGULATED CELL-DEATH
  • PARKINSONS-DISEASE
  • LEWY BODIES
  • CA2+ INFLUX
  • OLIGOMERS
  • ASSOCIATION
  • ASTROCYTES
  • MUTATION
  • FORMS

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