Parkinson’s disease-associated iPLA2-VIA/ PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Significance The mechanisms of α-synuclein aggregation and subsequent Lewy body formation are a key pathogenesis of Parkinson’s disease (PD). PARK14 -linked PD, which is caused by mutations of the iPLA2-VIA/PLA2G6 gene, exhibits a marked Lewy body pathology. iPLA2-VIA , which belongs to the phospholipase A 2 family, is another causative gene of neurodegeneration with brain iron accumulation (NBIA). Here, we demonstrate that iPLA2-VIA loss results in acyl-chain shortening in phospholipids, which affects ER homeostasis and neurotransmission and promotes α-synuclein aggregation. The administration of linoleic acid or the overexpression of C19orf12, one of the NBIA-causative genes, also suppresses the acyl-chain shortening by iPLA2-VIA loss. The rescue of iPLA2-VIA phenotypes by C19orf12 provides significant molecular insight into the underlying common pathogenesis of PD and NBIA.