Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.
Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.
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DOI：
10.1016/j.cell.2014.01.064
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发表时间：
2014-04-10
期刊：
影响因子：
64.5
通讯作者：
Dawson VL
中科院分区：
文献类型：
--
作者：
Martin I;Kim JW;Lee BD;Kang HC;Xu JC;Jia H;Stankowski J;Kim MS;Zhong J;Kumar M;Andrabi SA;Xiong Y;Dickson DW;Wszolek ZK;Pandey A;Dawson TM;Dawson VL
富含亮氨酸重复序列激酶2（LRRK2）的突变是家族性和散发性帕金森病（PD）的常见原因。升高的LRRK2激酶活性和神经变性是相关的，但连接LRRK2激酶活性和神经变性的磷酸底物尚不清楚。在这里，我们表明，核糖体蛋白s15是一个关键的致病LRRK2基板在果蝇和人类神经元PD模型。携带苏氨酸136至丙氨酸取代的磷酸缺陷s15拯救G2019S LRRK2转基因果蝇中的多巴胺神经元变性和年龄相关的运动缺陷，并显著减少G2019S LRRK2介导的人多巴胺和皮质神经元中的神经突损失和细胞死亡。值得注意的是，致病性LRRK2刺激帽依赖性和帽非依赖性mRNA翻译，并诱导果蝇中蛋白质合成的大量增加，这可以通过磷酸缺陷型T136A s15来预防。这些结果揭示了PD发病机制的一种新机制，与体内LRRK2激酶活性升高和蛋白质合成异常有关。
Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phospho-deficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation, and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phospho-deficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.
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