Saha Shamol, Guillily Maria D, Ferree Andrew, Lanceta Joel, Chan Diane, Ghosh Joy, Hsu Cindy H, Segal Lilach, Raghavan Kesav, Matsumoto Kunihiro, Hisamoto Naoki, Kuwahara Tomoki, Iwatsubo Takeshi, Moore Landon, Goldstein Lee, Cookson Mark, Wolozin Benjamin
Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
J Neurosci. 2009 Jul 22;29(29):9210-8. doi: 10.1523/JNEUROSCI.2281-09.2009.
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant familial Parkinson's disease. We generated lines of Caenorhabditis elegans expressing neuronally directed human LRRK2. Expressing human LRRK2 increased nematode survival in response to rotenone or paraquat, which are agents that cause mitochondrial dysfunction. Protection by G2019S, R1441C, or kinase-dead LRRK2 was less than protection by wild-type LRRK2. Knockdown of lrk-1, the endogenous ortholog of LRRK2 in C. elegans, reduced survival associated with mitochondrial dysfunction. C. elegans expressing LRRK2 showed rapid loss of dopaminergic markers (DAT::GFP fluorescence and dopamine levels) beginning in early adulthood. Loss of dopaminergic markers was greater for the G2019S LRRK2 line than for the wild-type line. Rotenone treatment induced a larger loss of dopamine markers in C. elegans expressing G2019S LRRK2 than in C. elegans expressing wild-type LRRK2; however, loss of dopaminergic markers in the G2019S LRRK2 nematode lines was not statistically different from that in the control line. These data suggest that LRRK2 plays an important role in modulating the response to mitochondrial inhibition and raises the possibility that mutations in LRRK2 selectively enhance the vulnerability of dopaminergic neurons to a stressor associated with Parkinson's disease.
富含亮氨酸重复激酶2（LRRK2）的突变会导致常染色体显性遗传性帕金森病。我们构建了表达神经元定向人类LRRK2的秀丽隐杆线虫品系。表达人类LRRK2可提高线虫对鱼藤酮或百草枯的存活率，这两种物质会导致线粒体功能障碍。G2019S、R1441C或激酶失活的LRRK2提供的保护作用小于野生型LRRK2。敲低线虫中LRRK2的内源性直系同源基因lrk-1，会降低与线粒体功能障碍相关的存活率。表达LRRK2的秀丽隐杆线虫从成年早期开始就出现多巴胺能标记物（多巴胺转运体::绿色荧光蛋白荧光和多巴胺水平）的快速丧失。G2019S LRRK2品系中多巴胺能标记物的丧失比野生型品系更严重。鱼藤酮处理使表达G2019S LRRK2的秀丽隐杆线虫中多巴胺标记物的丧失比表达野生型LRRK2的线虫更大；然而，G2019S LRRK2线虫品系中多巴胺能标记物的丧失与对照品系相比无统计学差异。这些数据表明，LRRK2在调节对线粒体抑制的反应中起重要作用，并增加了LRRK2突变选择性增强多巴胺能神经元对与帕金森病相关应激源易感性的可能性。
