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.