Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1
Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1
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DOI：
10.1093/hmg/ddm334
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发表时间：
2008-02-14
影响因子：
3.5
通讯作者：
Selkoe, Dennis J.
中科院分区：
文献类型：
--
作者：
Weihofen, Andreas;Ostaszewski, Beth;Selkoe, Dennis J.
普遍表达的基因PTEN诱导的激酶1（Pink 1）的突变导致常染色体隐性帕金森病。Pink 1编码一个假定的丝氨酸/苏氨酸激酶，具有N-末端线粒体靶向序列。通过Pink 1突变导致多巴胺能神经元选择性变性的机制尚不清楚。已在人脑中描述了全长前蛋白（66 kDa）和N-末端截短的成熟形式（55 kDa）。在这里，我们报告说，内源性66 kDa和55 kDa的粉红色的形式在培养的细胞是不排他的线粒体，但也发生在胞质和微粒体丰富的馏分。Pink 1 66 kDa是培养细胞中的主要同种型。使用无偏分析的免疫分离的Pink 1复合物的质谱，免疫共沉淀和热休克蛋白90抑制剂的研究，我们确定Pink 1作为一种新的Cdc 37/热休克蛋白90客户激酶。该伴侣系统影响Pink 1的亚细胞分布和66/55 kDa蛋白质比例。导致PD的Pink 1突变减少，而Parkin表达增加了Pink 1 66/55 kDa蛋白的比例，在生物化学上将Pink 1和Parkin联系起来，并突出了该比例与PD发病机制的潜在相关性。最后，我们记录了Parkin对Pink 1亚细胞分布的影响，为隐性PD的共同致病途径提供了进一步的证据。
Mutations in the ubiquitously expressed gene PTEN-induced kinase 1 (Pink1) cause autosomal recessive Parkinson's disease. Pink1 encodes a putative serine/threonine kinase with an N-terminal mitochondrial targeting sequence. The mechanism that leads to selective degeneration of dopaminergic neurons via Pink1 mutations is unknown. A full-length pre-protein (66 kDa) and an N-terminally truncated mature form (55 kDa) have been described in human brain. Here, we report that the endogenous 66 kDa and 55 kDa Pink1 forms in cultured cells are not exclusive to mitochondria but also occur in cytosolic and microsome-rich fractions. Pink1 66 kDa is the predominant isoform in cultured cells. Using unbiased analyses of immunoisolated Pink1 complexes by mass spectrometry, co-immunoprecipitation and Hsp90 inhibitor studies, we identify Pink1 as a novel Cdc37/Hsp90 client kinase. This chaperone system influences both the subcellular distribution and the 66/55 kDa protein ratio of Pink1. PD-causing Pink1 mutations decrease whereas Parkin expression increases the Pink1 66/55 kDa protein ratio, biochemically linking Pink1 and Parkin and highlighting the potential relevance of this ratio for PD pathogenesis. Finally, we document the influence of Parkin on Pink1 subcellular distribution, providing further evidence for a common pathogenic pathway in recessive PD.