The SNCA A53T mutation sensitizes human neurons and microglia to ferroptosis
The major pathological hallmarks of sporadic and familial forms of Parkinsons disease (PD) are the targeted and progressive loss of midbrain dopaminergic neurons (mDA), associated with systemic iron accumulation, -synuclein (syn) accumulation and aggregation, and lipid peroxidation amongst other reactive oxygen species (ROS) generation. Therapeutic strategies aimed towards dopamine restoration, syn removal and iron chelation have provided symptomatic relief but failed to prevent or slow disease progression. This is in part due to the lack of understanding of the exact pathways leading to neuronal death in PD. In this study, we investigate ferroptosis, a unique cell death mechanism sharing multiple features with PD pathology, as a relevant pathway with implications in disease pathogenesis. We identified an enrichment of ferroptosis genes dysregulated throughout PD postmortem brain samples and several neuronal and glial PD models. Using CRISPR/Cas9 technology, we generated a rapid iPSC-derived synucleinopathy neuronal model harbouring the SNCA A53T mutation and report increased ROS generation, reduced levels of antioxidant glutathione (GSH), impaired mitophagy and a heightened vulnerability to ferroptosis-induced lipid peroxidation and cell death. Critically, inhibition of the key lipid peroxidation enzyme and driver of ferroptosis, 15-lipoxygenase (15-LO), rescued synucleinopathy associated pathologies and prevented pathological syn oligomerisation in SNCA A53T neurons. Furthermore, we report enhanced microglial ferroptosis susceptibility in models of synucleinopathy. In summary, we highlight a new mechanism by which the familial PD-associated SNCA A53T mutation causes cell death and propose 15-LO inhibition as a tractable therapeutic opportunity in PD.