Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation

被引：184

作者：

Chen, Li ^{[1
]}

Periquet, Magali ^{[1
]}

Wang, Xu ^{[2
,3
]}

Negro, Alessandro ^{[4
]}

McLean, Pamela J. ^{[5
]}

Hyman, Bradley T. ^{[5
]}

Feany, Mel B. ^{[1
]}

机构：

[1] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Univ Padua, Dept Biochem, Padua, Italy

[5] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 119卷 / 11期

关键词：

PARKINSONS-DISEASE; DROSOPHILA MODEL; LEWY BODIES; RAT MODEL; MUTATION; MICE; NEURODEGENERATION; AGGREGATION; DIAGNOSIS; SER-129;

D O I：

10.1172/JCI39088

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wildtype human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.

引用

页码：3257 / 3265

页数：9

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