Nitrosative stress linked to sporadic Parkinson's disease:: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity
Nitrosative stress linked to sporadic Parkinson's disease:: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity
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DOI：
10.1073/pnas.0404161101
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发表时间：
2004-07-20
影响因子：
11.1
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Yao, DD;Gu, ZZ;Lipton, SA
许多遗传性和散发性神经退行性疾病的特点是异常蛋白的积累。散发性帕金森病是最常见的运动障碍，氧化应激和亚硝化应激被认为与疾病发病机制有关，但蛋白质聚集的确切分子基础尚不清楚。在常染色体隐性少年型帕金森病的病例中，E3泛素连接酶蛋白帕金的突变与多巴胺能神经元的死亡有关。在这里，我们在体外和体内都表明，亚硝化应激导致野生型帕金的s -亚硝基化，最初，E3连接酶-泛素-蛋白酶体降解途径急剧增加，随后减少。parkin的E3泛素连接酶活性的初始增加导致parkin的自身泛素化，随后抑制其活性，这将损害泛素化和清除parkin底物。因此，这些发现可能提供散发性帕金森病中自由基毒性和蛋白质积累之间的分子联系。
Many hereditary and sporadic neurodegenerative disorders are characterized by the accumulation of aberrant proteins. In sporadic Parkinson's disease, representing the most prevalent movement disorder, oxidative and nitrosative stress are believed to contribute to disease pathogenesis, but the exact molecular basis for protein aggregation remains unclear. In the case of autosomal recessive-juvenile Parkinsonism, mutation in the E3 ubiquitin ligase protein parkin is linked to death of dopaminergic neurons. Here we show both in vitro and in vivo that nitrosative stress leads to S-nitrosylation of wild-type parkin and, initially, to a dramatic increase followed by a decrease in the E3 ligase-ubiquitin-proteasome degradative pathway. The initial increase in parkin's E3 ubiquitin ligase activity leads to autoubiquitination of parkin and subsequent inhibition of its activity, which would impair ubiquitination and clearance of parkin substrates. These findings may thus provide a molecular link between free radical toxicity and protein accumulation in sporadic Parkinson's disease.