Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.
Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.
复制标题
致病性LRRK2负调节microRNA介导的翻译抑制。
作者：
富亮氨酸重复激酶2 （LRRK2）的功能获得突变导致家族性和散发性帕金森病（PD），其特征是年龄依赖性多巴胺能神经元（DN）变性。LRRK2作用的分子机制尚不清楚。在这里，我们发现LRRK2与microRNA （miRNA）途径相互作用以调节蛋白质合成。果蝇e2f1和dp mrna分别被let-7和miR-184*翻译抑制。致病性LRRK2会拮抗这些mirna，导致E2F1/DP的过量产生，而E2F1/DP先前与细胞周期和生存控制有关，并且在这里被证明是LRRK2发病的关键。let-7的基因缺失、安他哥米介导的let-7和miR-184*作用的阻断、dp靶保护因子的转基因表达，或用对let-7无反应的dp转基因替代内源性dp，都具有与致病性LRRK2相似的毒性作用。相反，增加let-7或miR-184*水平会减弱致病性LRRK2的作用。LRRK2与果蝇Argonaute-1 （dAgo1）或人类Argonaute-2 （hAgo2）的rna诱导沉默复合体（RISC）相关。在老龄果蝇脑中，dAgo1蛋白水平受LRRK2的负调控。此外，致病性LRRK2促进phospho-4E-BP1与hAgo2的关联。我们的研究结果表明，由miRNA通路损伤引起的E2F1/DP合成失调是LRRK2发病机制的一个关键事件，并提出了新的基于miRNA的治疗策略。
Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial as well as sporadic Parkinson’s disease (PD) characterized by age-dependent dopaminergic neuron (DN) degeneration. 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 mRNAs are translationally repressed by let-7 and miR-184*, respectively. Pathogenic LRRK2 antagonizes these miRNAs, leading to overproduction of E2F1/DP previously implicated in cell cycle and survival control, 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 replacing endogenous dp with a dp transgene non-responsive to let-7 all had similar toxic effects as pathogenic LRRK2. Conversely, increasing let-7 or miR-184* level attenuates pathogenic LRRK2 effects. LRRK2 associates with Drosophila Argonaute-1 (dAgo1) or human Argonaute-2 (hAgo2) of the RNA-induced silencing complex (RISC). In aged fly brain, dAgo1 protein level is negatively regulated by LRRK2. Further, pathogenic LRRK2 promotes the association of phospho-4E-BP1 with hAgo2. Our results implicate deregulated synthesis of E2F1/DP caused by miRNA pathway impairment as a key event in LRRK2 pathogenesis and suggest novel miRNA-based therapeutic strategies.
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影响因子：
25
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.0611671104
发表时间：
2007-02-27
影响因子：
11.1
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DOI：
10.1073/pnas.0507360102
发表时间：
2005-11-15
影响因子：
11.1
作者：
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通讯作者：
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