Parkinson’s disease-associated PLA2G6 protects IP3R1 protein to control ER-mitochondria tethering and Ca2+ transfer

Abstract Mutations in the phospholipase A2 group VI ( PLA2G6 ) gene have been linked to autosomal recessive Parkinson’s disease (PD), yet the molecular mechanisms remain poorly understood. This study provides the in vitro and in vivo evidence, specifically in dopaminergic neurons derived from patients with PD, that PLA2G6 loss-of-function disrupts the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), a critical regulator of Ca 2+ transfer and energy homeostasis. This study demonstrates that the PLA2G6 protein localizes to the MAM and physically associates with the IP3R1-GRP75-VDAC1 complex. PLA2G6 deficiency destabilizes this complex, accelerating IP3R1 degradation, which in turn reduces ER-mitochondria contacts and impairs Ca 2+ transfer. Notably, introducing a MAM linker restores the phenotypes caused by PLA2G6 loss. In iPSCs-derived dopaminergic neurons from patients with PD harboring PLA2G6 mutations, the structural and functional disruption of the MAM is further confirmed, underscoring its role in PD pathogenesis. These findings uncover the pivotal function of PLA2G6 within the MAM and suggest that modulating inter-organelle contacts could be a therapeutic strategy for correcting PD’s ion channel dysfunction and energy imbalances.