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

• Mori, Akio

• Hatano, Taku

• Inoshita, Tsuyoshi

• Shiba-Fukushima, Kahori

• Koinuma, Takahiro

• Meng, Hongrui

• Kubo, Shin-ichiro

• Spratt, Spencer

• Cui, Changxu

• Yamashita, Chikara

• Miki, Yoshimi

• Yamamoto, Kei

• Hirabayashi, Tetsuya

• Murakami, Makoto

• Takahashi, Yoshikazu

• Shindou, Hideo

• Nonaka, Takashi

• Hasegawa, Masato

• Okuzumi, Ayami

• Imai, Yuzuru

• Hattori, Nobutaka

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences of the United States of America

  Proceedings of the National Academy of Sciences of the United States of America 116 (41), 20689-20699, 2019-09-23

  National Academy of Sciences

キーワード

• Parkinson’s disease
• lipids
• Drosophila
• ER stress
• α-synuclein

詳細情報

• CRID: 1050570620371819648
• NII論文ID: 120007132272
• NII書誌ID: AA11726874
• ISSN: 10916490
• ISSN: 00278424
• DOI: 10.1073/pnas.1902958116
• Web Site: http://repo.lib.tokushima-u.ac.jp/115697
• Web Site: http://www.pnas.org/syndication/doi/10.1073/pnas.1902958116
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.1902958116
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN