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

• DOI: 10.1073/pnas.1902958116
• Publication Date: 2019-09-24T00:35:32Z
• Authors: Akio Mori; Taku Hatano; Tsuyoshi Inoshita; Kahori Shiba-Fuku...; Takahiro Koinuma; Hongrui Meng; Shin-ichiro Kubo; Spencer Spratt; Changxu Cui; Chikara Yamashita; Yoshimi Miki; Kei Yamamoto; Tetsuya Hirabayashi; Makoto Murakami; Yoshikazu Takahashi; Hideo Shindou; Takashi Nonaka; Masato Hasegawa; Ayami Okuzumi; Yuzuru Imai; Nobutaka Hattori
• Keywords: Male; 0301 basic medicine; 572; Synaptic Transmission; lipids; Animals, Genetically Modified; Group VI Phospholipases A2; Mitochondrial Proteins; 03 medical and health sciences; α-synuclein; Animals; Drosophila Proteins; Group X Phospholipases A2; Humans; Phospholipids; Dopaminergic Neurons; Cell Membrane; Brain; Parkinson Disease; Endoplasmic Reticulum Stress; Mitochondria; 3. Good health; Drosophila melanogaster; PNAS Plus; Nerve Degeneration; Parkinson’s disease; alpha-Synuclein; Drosophila; Female; ER stress

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.