LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans.
LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans.
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DOI：
10.1523/jneurosci.2281-09.2009
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发表时间：
2009-07-22
期刊：
影响因子：
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通讯作者：
Wolozin B
中科院分区：
文献类型：
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作者：
Saha S;Guillily MD;Ferree A;Lanceta J;Chan D;Ghosh J;Hsu CH;Segal L;Raghavan K;Matsumoto K;Hisamoto N;Kuwahara T;Iwatsubo T;Moore L;Goldstein L;Cookson M;Wolozin B
富含亮氨酸的重复序列激酶2（LRRK 2）突变导致常染色体显性遗传家族性帕金森病。我们生成了C的行。表达神经定向的人LRRK 2的线虫。表达人LRRK 2表达增加响应鱼藤酮或百草枯的线虫存活率，鱼藤酮或百草枯是引起线粒体功能障碍的药剂。G2019 S、R1441 C或激酶死亡的LRRK 2的保护作用低于野生型LRRK 2的保护作用。C中LRRK 2的内源性直系同源物lrk-1的敲除。elegans，与线粒体功能障碍相关的生存减少。C.表达LRRK 2的秀丽隐杆线虫在成年早期表现出多巴胺能标记物（DAT-GFP荧光和多巴胺水平）的快速丧失。G2019 S LRRK 2系的多巴胺能标志物的损失大于WT系。鱼藤酮处理诱导C.表达G2019 SLRRK 2的线虫比表达C.表达WT LRRK 2的线虫;然而，G2019 S LRRK 2线虫系中多巴胺能标记物的损失与对照系中的多巴胺能标记物的损失没有统计学差异。这些数据表明，LRRK 2在调节线粒体抑制反应中起着重要作用，并提出了LRRK 2突变选择性增强多巴胺能神经元对帕金森病相关应激源的脆弱性的可能性。
Mutations in leucine rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson’s disease. We generated lines of C. elegans expressing neuronally directed human LRRK2. Expressing human LRRK2 expression 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 orthologue 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 WT line. Rotenone treatment induced a larger loss of dopamine markers in C. elegans expressing G2019S LRRK2 than in C. elegans expressing WT LRRK2; however loss of dopaminergic markers in the G2019S LRRK2 nematode lines was not statistically different than 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.