“富含亮氨酸的重復(fù)段激酶-2” (LRRK2)所發(fā)生的突變已被與家族性和偶發(fā)性帕金森氏癥聯(lián)系在一起，但其生化功能卻一直不清楚?，F(xiàn)在,，LRRK2的一個生化功能已被發(fā)現(xiàn)。果蠅和人類的LRRK2都被發(fā)現(xiàn)拮抗由微RNA調(diào)控的對E2F1 和 DP轉(zhuǎn)錄因子的翻譯抑制,。LRRK2與由RNA誘導的沉寂復(fù)合物組分Argonaute發(fā)生相互作用,，來拮抗其對蛋白翻譯的抑制效應(yīng)?；铙w遺傳研究表明，E2F1/DP上調(diào)在調(diào)控突變體LRRK2的發(fā)病機理中扮演一個關(guān)鍵角色,。
這些發(fā)現(xiàn)表明,，受損的、由微RNA調(diào)控的沉寂作用與特定微RNA目標的失控表達之間有一個聯(lián)系,，它能造成帕金森氏癥的發(fā)?。欢疫@些發(fā)現(xiàn)還提出了基于微RNA的可能治療方法,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
