Post-transcriptional Regulation of α-Synuclein Expression by mir-7 and mir-153
Post-transcriptional Regulation of α-Synuclein Expression by mir-7 and mir-153
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DOI：
10.1074/jbc.m109.086827
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发表时间：
2010-04-23
影响因子：
4.8
通讯作者：
Doxakis, Epaminondas
中科院分区：
文献类型：
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作者：
Doxakis, Epaminondas
遗传和生物化学研究已经确立了α-突触核蛋白积累在帕金森病发病机制中的核心作用。在这里，已经鉴定了两种microRNA，即mir-7和mir-153，以调节转录后的α-突触核蛋白水平。这些microRNA特异性结合到α-突触核蛋白的3 '-非翻译区，并下调其mRNA和蛋白质水平，其作用是累加的。它们主要在大脑中表达，其模式反映了突触核蛋白在不同组织中以及在神经元发育期间的表达，表明它们在产生的α-突触核蛋白的量中起调节作用。mir-7和mir-153的过表达显著降低了内源性α-突触核蛋白水平，而mir-7和mir-153的抑制增强了原代神经元中携带α-突触核蛋白3 '-非翻译区的荧光素酶构建体的翻译。这些发现揭示了α-突触核蛋白调节的一个重要的额外机制，并指出了降低家族性或散发性帕金森病患者内源性α-突触核蛋白水平的新治疗方案。
Genetic and biochemical studies have established a central role for alpha-synuclein accumulation in the pathogenesis of Parkinson disease. Here, two microRNAs, namely mir-7 and mir-153, have been identified to regulate alpha-synuclein levels post-transcriptionally. These microRNAs bind specifically to the 3'-untranslated region of alpha-synuclein and down-regulate its mRNA and protein levels, with their effect being additive. They are expressed predominantly in the brain with a pattern that mirrors synuclein expression in different tissues as well as during neuronal development, indicating that they play a tuning role in the amount of alpha-synuclein produced. Overexpression of mir-7 and mir-153 significantly reduces endogenous alpha-synuclein levels, whereas inhibition of mir-7 and mir-153 enhances translation of a luciferase construct bearing the alpha-synuclein 3'-untranslated region in primary neurons. These findings reveal a significant additional mechanism by which alpha-synuclein is regulated and point toward new therapeutic regimes for lowering endogenous alpha-synuclein levels in patients with familial or sporadic Parkinson disease.