Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
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DOI：
10.1038/ncomms11792
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发表时间：
2016-06-07
影响因子：
16.6
通讯作者：
Ross CA
中科院分区：
文献类型：
--
作者：
Nucifora FC Jr;Nucifora LG;Ng CH;Arbez N;Guo Y;Roby E;Shani V;Engelender S;Wei D;Wang XF;Li T;Moore DJ;Pletnikova O;Troncoso JC;Sawa A;Dawson TM;Smith W;Lim KL;Ross CA
帕金森病（PD）的一种常见遗传形式是由LRRK2突变引起的。我们确定WSB 1作为LRRK2相互作用蛋白。WSB 1通过K27和K29连接链泛素化LRRK2，导致LRRK2聚集和原代神经元中的神经元保护以及G2019S LRRK2的果蝇模型。敲低内源性WSB 1会加剧神经元和果蝇模型中的突变型LRRK2神经元毒性，表明内源性WSB 1在调节LRRK2细胞毒性中的作用。WSB 1存在于人PD死后组织的路易体中。这些数据证明了WSB 1在突变型LRRK2发病机制中的作用，并表明参与散发性PD的路易体病理学。我们的数据表明泛素K27和K29连接在PD中的作用，并表明泛素化可能是PD中聚集和神经元保护的信号，这可能与其他神经退行性疾病相关。最后，我们的研究确定了一个新的治疗PD的目标。 LRRK2的突变与帕金森病有关。在这里，作者将WSB 1鉴定为LRRK2相互作用蛋白，并发现它通过泛素K27和K29连接促进LRRK2在初级神经元和果蝇模型中的聚集。
A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD. Mutations in LRRK2 are linked to Parkinson's Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.