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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
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Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.

机译：富含亮氨酸的重复激酶2中的帕金森氏病相关突变增强了激酶活性。

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摘要

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that LRRK2 mutations are the most common yet identified determinant of PD susceptibility, transmitted in an autosomal-dominant mode of inheritance. Herein, we characterize the LRRK2 gene and transcript in human brain and subclone the predominant ORF. Exogenously expressed LRRK2 protein migrates at approximately 280 kDa and is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Familial-linked mutations G2019S or R1441C do not have an obvious effect on protein steady-state levels, turnover, or localization. However, in vitro kinase assays using full-length recombinant LRRK2 reveal an increase in activity caused by familial-linked mutations in both autophosphorylation and the phosphorylation of a generic substrate. These results suggest a gain-of-function mechanism for LRRK2-linked disease with a central role for kinase activity in the development of PD.
机译：富含亮氨酸的重复激酶2基因（LRRK2）中的突变会导致迟发性帕金森氏病（PD），其临床表现与特发性PD难以区分。初步研究表明，LRRK2突变是PD易感性最常见的决定因素，以常染色体显性遗传方式传播。本文中，我们表征了人脑中的LRRK2基因和转录本，并克隆了主要的ORF。外源表达的LRRK2蛋白以大约280 kDa的速率迁移，并主要存在于细胞质中，但也与线粒体外膜相关。家族相关的突变G2019S或R1441C对蛋白质稳态水平，周转率或定位没有明显影响。但是，使用全长重组LRRK2进行的体外激酶测定显示，由于自身磷酸化和通用底物的磷酸化中的家族连锁突变引起的活性增加。这些结果表明LRRK2连锁疾病的功能获得机制，在PD的发展中激酶活性的核心作用。

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