Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition

Laura Mahoney-Sanchez, Hind Bouchaoui, Ibrahim Boussaad, Aurélie Jonneaux, Kelly Timmerman, Olivier Berdeaux, Scott Ayton, Rejko Krüger, James A. Duce*, David Devos*, Jean Christophe Devedjian

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients’ small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance.

Original languageEnglish
Article number111231
JournalCell Reports
Volume40
Issue number8
DOIs
Publication statusPublished - 23 Aug 2022

Keywords

  • alpha synuclein
  • cell death
  • CP: Molecular biology
  • CP: Neuroscience
  • ether phospholipids
  • ferroptosis
  • lipid peroxidation
  • Parkinson's disease

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