专题：Nature系列
“富含亮氨酸的重复段激酶-2” (LRRK2)所发生的突变已被与家族性和偶发性帕金森氏症联系在一起，但其生化功能却一直不清楚。现在，LRRK2的一个生化功能已被发现。果蝇和人类的LRRK2都被发现拮抗由微RNA调控的对E2F1 和 DP转录因子的翻译抑制。LRRK2与由RNA诱导的沉寂复合物组分Argonaute发生相互作用，来拮抗其对蛋白翻译的抑制效应。活体遗传研究表明，E2F1/DP上调在调控突变体LRRK2的发病机理中扮演一个关键角色。
这些发现表明，受损的、由微RNA调控的沉寂作用与特定微RNA目标的失控表达之间有一个联系，它能造成帕金森氏症的发病；而且这些发现还提出了基于微RNA的可能治疗方法。
推荐原文出处：
Nature doi:10.1038/nature09191
Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression
Stephan Gehrke,Yuzuru Imai,Nicholas Sokol" Bingwei Lu
Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial as well as sporadic Parkinson’s disease characterized by age-dependent degeneration of dopaminergic neurons1, 2. The molecular mechanism of LRRK2 action is not known. Here we show that LRRK2 interacts with the microRNA (miRNA) pathway to regulate protein synthesis. Drosophila e2f1 and dp messenger RNAs are translationally repressed by let-7 and miR-184*, respectively. Pathogenic LRRK2 antagonizes these miRNAs, leading to the overproduction of E2F1/DP, previously implicated in cell cycle and survival control3 and shown here to be critical for LRRK2 pathogenesis. Genetic deletion of let-7, antagomir-mediated blockage of let-7 and miR-184* action, transgenic expression of dp target protector, or replacement of endogenous dp with a dp transgene non-responsive to let-7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of let-7 or miR-184* attenuated pathogenic LRRK2 effects. LRRK2 associated with Drosophila Argonaute-1 (dAgo1) or human Argonaute-2 (hAgo2) of the RNA-induced silencing complex (RISC). In aged fly brain, dAgo1 protein level was negatively regulated by LRRK2. Further, pathogenic LRRK2 promoted the association of phospho-4E-BP1 with hAgo2. Our results implicate deregulated synthesis of E2F1/DP caused by the miRNA pathway impairment as a key event in LRRK2 pathogenesis and suggest novel miRNA-based therapeutic strategies.
