| ID | 115697 |
| Author |
Mori, Akio
Juntendo University
Hatano, Taku
Juntendo University
Inoshita, Tsuyoshi
Juntendo University
Shiba-Fukushima, Kahori
Juntendo University
Koinuma, Takahiro
Juntendo University
Meng, Hongrui
Juntendo University
Kubo, Shin-ichiro
Juntendo University
Spratt, Spencer
Juntendo University
Cui, Changxu
Juntendo University
Yamashita, Chikara
Juntendo University
Miki, Yoshimi
The University of Tokyo
Yamamoto, Kei
Tokushima University|Japan Agency for Medical Research and Development
Tokushima University Educator and Researcher Directory
KAKEN Search Researchers
Hirabayashi, Tetsuya
Tokyo Metropolitan Institute of Medical Science
Murakami, Makoto
The University of Tokyo|Japan Agency for Medical Research and Development
Takahashi, Yoshikazu
Japan Agency for Medical Research and Development|National Center for Global Health and Medicine
Shindou, Hideo
Japan Agency for Medical Research and Development|National Center for Global Health and Medicine|The University of Tokyo
Nonaka, Takashi
Tokyo Metropolitan Institute of Medical Science
Hasegawa, Masato
Tokyo Metropolitan Institute of Medical Science
Okuzumi, Ayami
Juntendo University
Imai, Yuzuru
Juntendo University
Hattori, Nobutaka
Juntendo University
|
| Keywords | Parkinson’s disease
lipids
Drosophila
ER stress
α-synuclein
|
| Content Type |
Journal Article
|
| Description | 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.
|
| Journal Title |
Proceedings of the National Academy of Sciences of the United States of America
|
| ISSN | 10916490
|
| NCID | AA11726874
AA12104563
|
| Publisher | National Academy of Sciences
|
| Volume | 116
|
| Issue | 41
|
| Start Page | 20689
|
| End Page | 20699
|
| Published Date | 2019-09-23
|
| Rights | This open access article is distributed under Creative Commons Attribution-NonCommercial-
NoDerivatives License 4.0 (CC BY-NC-ND)(https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| EDB ID | |
| DOI (Published Version) | |
| URL ( Publisher's Version ) | |
| FullText File | |
| language |
eng
|
| TextVersion |
Publisher
|
| departments |
Bioscience and Bioindustry
|
