RRC ID 59152
Author Mori A, Hatano T, Inoshita T, Shiba-Fukushima K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui C, Yamashita C, Miki Y, Yamamoto K, Hirabayashi T, Murakami M, Takahashi Y, Shindou H, Nonaka T, Hasegawa M, Okuzumi A, Imai Y, Hattori N.
Title Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling.
Journal Proc Natl Acad Sci U S A
Abstract Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson's disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA-deficient Drosophila 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 iPLA2-VIA 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 iPLA2-VIA-deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA 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.
Volume 116(41)
Pages 20689-20699
Published 2019-10-8
DOI 10.1073/pnas.1902958116
PII 1902958116
PMID 31548400
PMC PMC6789907
MeSH Animals Animals, Genetically Modified Brain / metabolism Brain / pathology* Cell Membrane / metabolism Cell Membrane / pathology* Dopaminergic Neurons / metabolism Dopaminergic Neurons / pathology* Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster Endoplasmic Reticulum Stress Female Group VI Phospholipases A2 / genetics Group VI Phospholipases A2 / metabolism Group X Phospholipases A2 / genetics Group X Phospholipases A2 / metabolism* Humans Male Mitochondria / metabolism Mitochondria / pathology Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism Nerve Degeneration / metabolism Nerve Degeneration / pathology* Parkinson Disease / metabolism Parkinson Disease / pathology* Phospholipids / metabolism Synaptic Transmission alpha-Synuclein / chemistry* alpha-Synuclein / genetics alpha-Synuclein / metabolism
IF 9.58
Times Cited 4