Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated α- synuclein implies Lewy body biogenesis
Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated α- synuclein implies Lewy body biogenesis
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DOI：
10.1074/jbc.m700422200
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发表时间：
2007-05-11
影响因子：
4.8
通讯作者：
Wang, Guanghui
中科院分区：
文献类型：
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作者：
Liu, Chao;Fei, Erkang;Wang, Guanghui
α-突触核蛋白（alpha-synuclein，alpha-syn）和泛素（ubiquitin，Ub）是沉积在路易体（Lewy bodies，LB）和路易神经突（Lewy neurites）中的主要蛋白成分，是帕金森病（idiopathic Parkinson disease，PD）的病理标志。LB中几乎90%的α-syn在丝氨酸129（Ser（129））处磷酸化。然而，Ser（129）-磷酸化的α-syn在LB生物发生中的作用仍不清楚。在这里，我们表明，与野生型（WT）alpha-syn和Ub的共表达相比，neuro 2a细胞中磷酸模拟突变体alpha-syn（S129 D）和Ub的共表达导致Ub缀合物的增加和遍在蛋白化内含物的形成。此外，S129 D α-syn未能增加Ub-缀合物，并在K63 R突变体Ub存在下形成泛素化包涵体。此外，与WT alpha-syn相比，S129 D alpha-syn在用H2 O2和血清剥夺处理的neuro 2a细胞中增加了其自身的细胞质和神经炎聚集体。这些结果表明，Ser（129）-磷酸化的α-syn对Lys（63）-连接的Ub-缀合物的贡献及其自身的聚集可能参与帕金森病和其他相关突触核蛋白病中LB的生物发生。
alpha-Synuclein (alpha-syn) and ubiquitin (Ub) are major protein components deposited in Lewy bodies (LBs) and Lewy neurites, which are pathologic hallmarks of idiopathic Parkinson disease (PD). Almost 90% of alpha-syn in LBs is phosphorylated at serine 129 (Ser(129)). However, the role of Ser(129)-phosphorylated alpha-syn in the biogenesis of LBs remains unclear. Here, we show that compared with coexpression of wild type(WT) alpha-syn and Ub, coexpression of phospho-mimic mutant alpha-syn (S129D) and Ub in neuro2a cells results in an increase of Ub-conjugates and the formation of ubiquitinated inclusions. Furthermore, S129D alpha-syn fails to increase the Ub-conjugates and form ubiquitinated inclusions in the presence of a K63R mutant Ub. In addition, as compared with WT alpha-syn, S129D alpha-syn increased cytoplasmic and neuritic aggregates of itself in neuro2a cells treated with H2O2 and serum deprivation. These results suggest that the contribution of Ser(129)-phosphorylated alpha-syn to the Lys(63)-linked Ub-conjugates and aggregation of itself may be involved in the biogenesis of LBs in Parkinson disease and other related synucleinopathies.