Phosphorylation of a-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease

被引：10

作者：

Matsui, Hideaki ^{[1
,2
]}

Ito, Shinji ^{[3
]}

Matsui, Hideki ^{[4
]}

Ito, Junko ^{[5
]}

Gabdulkhaev, Ramil ^{[5
]}

Hirose, Mika ^{[6
]}

Yamanaka, Tomoyuki ^{[2
]}

Koyama, Akihide ^{[7
]}

Kato, Taisuke ^{[8
]}

Tanaka, Maiko ^{[4
]}

Uemura, Norihito ^{[1
,2
,9
]}

Matsui, Noriko

Hirokawa, Sachiko ^{[10
]}

Yoshihama, Maki ^{[11
]}

Shimozawa, Aki ^{[12
]}

Kubo, Shin-ichiro ^{[4
,13
]}

Iwasaki, Kenji ^{[6
,14
]}

Hasegawa, Masato ^{[12
]}

Takahashi, Ryosuke ^{[9
]}

Hirai, Keisuke ^{[4
]}

Kakita, Akiyoshi ^{[5
]}

Onodera, Osamu ^{[10
]}

机构：

[1] Niigata Univ, Ctr Transdisciplinary Res, Dept Neurosci Dis, Niigata 9518585, Japan

[2] Niigata Univ, Brain Res Inst, Dept Neurosci Dis, Niigata 9518585, Japan

[3] Kyoto Univ, Med Res Support Ctr, Grad Sch Med, Kyoto 6068501, Japan

[4] Takeda Pharmaceut Co Ltd, Neurosci Drug Discovery Unit, Res, Fujisawa 2518555, Japan

[5] Niigata Univ, Brain Res Inst, Dept Pathol, Niigata 9518585, Japan

[6] Osaka Univ, Inst Prot Res, Suita, Osaka 5650871, Japan

[7] Niigata Univ, Dept Legal Med, Grad Sch Med & Dent Sci, Niigata 9518585, Japan

[8] Niigata Univ, Brain Res Inst, Dept Syst Pathol Neurol Disorders, Brain Sci Branch, Niigata 9518585, Japan

[9] Kyoto Univ, Dept Neurol, Grad Sch Med, Kyoto 6068507, Japan

[10] Niigata Univ, Brain Res Inst, Dept Neurol, Clin Neurosci Branch, Niigata 9518585, Japan

[11] Univ Miyazaki, Frontier Sci Res Ctr, Miyazaki 8891692, Japan

[12] Tokyo Metropolitan Inst Med Sci, Dementia Res Project, Tokyo 1568506, Japan

[13] Eisei Hosp, Parkinsons Dis Ctr, Dept Neurol, Tokyo 1930942, Japan

[14] Univ Tsukuba, Life Sci Ctr Survival Dynam, Tsukuba Adv Res Alliance, Tsukuba 3058577, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 23期

关键词：

Parkinson's disease; & alpha; -synuclein; zebrafish; ALPHA-SYNUCLEIN; GLUCOCEREBROSIDASE MUTATIONS; DUPLICATION;

D O I：

10.1073/pnas.2214652120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

a-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 a-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of a-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of a-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 a-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 a-synuclein phosphorylation at T64 in PD.

引用

页数：8

共 48 条

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