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

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. [Display omitted] • α-Synuclein levels determine sensitivity of dopaminergic neurons to ferroptosis • α-Synuclein regulates the synthesis of ether-linked phospholipids • Elevated α-synuclein expression increases lipid peroxidation and ferroptosis risk The pathological mechanisms underlying α-synuclein toxicity and neuronal cell death in Parkinson's disease are unclear. Mahoney-Sanchez et al. present a direct association between endogenous α-synuclein levels and the sensitivity of dopaminergic neurons to lipid peroxidation and ferroptosis via modulation of plasma membrane ether-linked phospholipids. [ABSTRACT FROM AUTHOR]