Kinase activity is required for the toxic effects of mutant LRRK2/dardarin
Kinase activity is required for the toxic effects of mutant LRRK2/dardarin
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DOI：
10.1016/j.nbd.2006.04.001
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发表时间：
2006-08-01
影响因子：
6.1
通讯作者：
Cookson, Mark R.
中科院分区：
文献类型：
--
作者：
Greggio, Elisa;Jain, Shushant;Cookson, Mark R.
编码dardarin的LRRK2基因突变主要导致遗传性帕金森病（PD）。Dardarin是一种大的蛋白质，在整个基因中发现突变，包括激酶结构域。然而，目前尚不清楚激酶活性是否对致病性突变的破坏性影响很重要。在这项研究中，我们注意到两种细胞表型与突变的达旦素相关。首先，致病性突变增加了达达素形成包涵体的倾向。其次，神经元和神经元细胞系在表达突变蛋白后发生细胞死亡。通过将激酶结构域替换为“激酶死亡”版本来控制活性，可阻断包涵体的形成，并大大延迟细胞死亡。这预示着激酶抑制剂将成为LRRK2突变患者和散发性PD患者的有效治疗药物。我们还发现，在人类中脑神经元中表达了达旦苷蛋白，并且在一些路易小体中也发现了c端表位。Elsevier Inc.出版。
Mutations in the LRRK2 gene, coding for dardarin, cause dominantly inherited Parkinson's disease (PD). Dardarin is a large protein, and mutations are found throughout the gene including the kinase domain. However, it is not clear if kinase activity is important for the damaging effects of pathogenic mutations. In this study, we noted two cellular phenotypes associated with mutant dardarin. First, pathogenic mutations increase the tendency of dardarin to form inclusion bodies. Secondly, neurons and neuronal cell lines undergo cell death after expression of mutant protein. Manipulating activity by replacing the kinase domain with a 'kinase-dead' version blocks inclusion body formation and strongly delays cell death. This predicts that kinase inhibitors will be useful therapeutic agents in patients with LRRK2 mutations and, perhaps, in sporadic PD. We also show that dardarin protein is expressed within human midbrain neurons and that C-terminal epitopes are also found in some Lewy bodies. Published by Elsevier Inc.