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 or-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing or-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated or-syn-uclein 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 resis-tance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of or-synuclein (or-syn). These results provide a molecular mechanism linking or-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance.

Automated summary

This study uses human dopaminergic neuronal models to demonstrate that the expression levels of α-synuclein determine the sensitivity of dopaminergic neurons to ferroptosis. Reduction of α-synuclein expression leads to evasion of ferroptosis, while increased expression causes increased vulnerability to lipid peroxidation and ferroptosis in neuronal precursor cells. These findings provide insight into the molecular mechanism linking α-synuclein levels to the sensitivity of dopaminergic neurons to ferroptosis and suggest potential therapeutic implications.