PUBLICATION
Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease
- Authors
- Matsui, H., Ito, S., Matsui, H., Ito, J., Gabdulkhaev, R., Hirose, M., Yamanaka, T., Koyama, A., Kato, T., Tanaka, M., Uemura, N., Matsui, N., Hirokawa, S., Yoshihama, M., Shimozawa, A., Kubo, S.I., Iwasaki, K., Hasegawa, M., Takahashi, R., Hirai, K., Kakita, A., Onodera, O.
- ID
- ZDB-PUB-230531-35
- Date
- 2023
- Source
- Proceedings of the National Academy of Sciences of the United States of America 120: e2214652120e2214652120 (Journal)
- Registered Authors
- Matsui, Hideaki
- Keywords
- Parkinson's disease, zebrafish, α-synuclein
- MeSH Terms
-
- Brain/metabolism
- Humans
- Lewy Bodies/metabolism
- Parkinson Disease*/metabolism
- Phosphorylation
- alpha-Synuclein/genetics
- alpha-Synuclein/metabolism
- PubMed
- 37252975 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Matsui, H., Ito, S., Matsui, H., Ito, J., Gabdulkhaev, R., Hirose, M., Yamanaka, T., Koyama, A., Kato, T., Tanaka, M., Uemura, N., Matsui, N., Hirokawa, S., Yoshihama, M., Shimozawa, A., Kubo, S.I., Iwasaki, K., Hasegawa, M., Takahashi, R., Hirai, K., Kakita, A., Onodera, O. (2023) Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America. 120:e2214652120e2214652120.
Abstract
α-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of α-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of α-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of α-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of α-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of α-synuclein phosphorylation at T64 in PD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping