Phosphorylation of α-Synuclein at T64 Results in Distinct Oligomers and Exerts Toxicity in models of Parkinson's Disease

Proc. Natl. Acad. Sci. USA 2023 Jun 6;120(23):e2214652120. doi: 10.1073/pnas.2214652120. Epub 2023 May 30.

Matsui H1,2, Ito S3, Matsui H4, Ito J5, Gabdulkhaev R5, Hirose M6, Yamanaka T2, Koyama A7, Kato T8, Tanaka M4, Uemura N9, Matsui N1,2, Hirokawa S10, Yoshihama M11, Shimozawa A12, Kubo SI4,13, Iwasaki K6,14, Hasegawa M12, Takahashi R9, Hirai K4, Kakita A5, Onodera O10.

1Department of Neuroscience of Disease, Center for Transdisciplinary Research, Niigata University.

2Department of Neuroscience of Disease, Brain Research Institute, Niigata University.

3Medical Research Support Center, Graduate School of Medicine, Kyoto University.

4Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited.

5Department of Pathology, Brain Research Institute, Niigata University.

6Institute for Protein Research, Osaka University.

7Department of Legal Medicine, Niigata University Graduate School of Medical and Dental Science.

8Department of System Pathology for Neurological Disorders, Brain Science Branch, Brain Research Institute, Niigata University.

9Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto University.

10Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University.

11Frontier Science Research Center, University of Miyazaki.

12Dementia Research Project, Tokyo Metropolitan Institute of Medical Science.

13Department of Neurology, Parkinson's Disease Center, Eisei Hospital.

14Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba.

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.

*Reprinted under a CC BY NC ND 4.0 license.


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