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

Abstract

Mutations in the <i>iPLA2-VIA/PLA2G6</i> gene are responsible for <i>PARK14</i>-linked Parkinson's disease (PD) with α-synucleinopathy. However, it is unclear how <i>iPLA2-VIA</i> mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that <i>iPLA2-VIA</i>-deficient <i>Drosophila</i> exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by <i>iPLA2-VIA</i> loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria-ER contact site-resident protein C19orf12 in <i>iPLA2-VIA</i>-deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, <i>iPLA2-VIA</i> A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by <i>iPLA2-VIA</i> loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.