α-Synuclein is phosphorylated in synucleinopathy lesions
α-Synuclein is phosphorylated in synucleinopathy lesions
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DOI：
10.1038/ncb748
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发表时间：
2002-02-01
影响因子：
21.3
通讯作者：
Iwatsubo, T
中科院分区：
文献类型：
--
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
大量的突触前脑蛋白α-突触核蛋白以纤维状聚集体的形式沉积在神经元或神经胶质细胞中，是神经退行性疾病的一种标志性病变。这些疾病包括帕金森氏病(PD)、路易体痴呆(DLB)和多系统萎缩，统称为联核病(1，2)。重要的是，在一些家族性帕金森病家系中发现了α-突触核蛋白基因的错义突变，这与帕金森病和其他突触核病的发病机制密切相关(3)。然而，在受影响的大脑中聚集α-突触核蛋白的特定翻译后修饰还没有被确定。在这里，我们通过质谱分析和对一种特异性识别α-突触核蛋白的磷酸丝氨酸129的抗体的研究表明，在突触核病的病变中，这种残基被选择性地和广泛地磷酸化。此外，α-突触核蛋白在Ser129处的磷酸化在体外促进了纤维的形成。这些结果强调了丝状蛋白的磷酸化在神经退行性疾病发病机制中的重要性。
The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies(1,2). Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies(3). However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.