Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice
Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice
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DOI：
10.1073/pnas.1004676107
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发表时间：
2010-05-25
影响因子：
11.1
通讯作者：
Shen, Jie
中科院分区：
文献类型：
--
作者：
Tong, Youren;Yamaguchi, Hiroo;Shen, Jie
富含亮氨酸重复序列激酶2（LRRK 2）的突变是帕金森病最常见的遗传原因。LRRK 2是一个大的蛋白质，含有一个小的GT3结构域和一个激酶结构域，但其生理作用尚不清楚。为了鉴定LRRK 2在体内的正常功能，我们产生了两个独立的种系缺失小鼠品系。LRRK 2（-/-）小鼠的多巴胺能系统表现正常，多巴胺能神经元的数量和纹状体多巴胺的水平没有变化。然而，与其他器官相比，LRRK 2-/-肾脏遭受最大的LRRK损失，在20月龄时发生α-突触核蛋白和泛素化蛋白的显著积累和聚集。自噬-溶酶体途径在LRRK 2不存在的情况下也受损，如脂褐质颗粒的积累以及LC 3-II和p62水平的改变所示。此外，LRRK 2的缺失显著增加了凋亡性细胞死亡、炎症反应和氧化损伤。总的来说，我们的研究结果表明，LRRK 2在衰老过程中蛋白质稳态的调节中起着重要和意想不到的作用，并表明LRRK 2突变可能通过蛋白质降解途径的损伤引起帕金森病和细胞死亡，导致α-突触核蛋白随着时间的推移积累和聚集。
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent linesofgerm-line deletion mice. The dopaminergic system of LRRK2(-/-) mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2-/- kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of alpha-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to alpha-synuclein accumulation and aggregation over time.