Junn Eunsung, Lee Kang-Woo, Jeong Byeong Seon, Chan Teresa W, Im Joo-Young, Mouradian M Maral
Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13052-7. doi: 10.1073/pnas.0906277106. Epub 2009 Jul 23.
alpha-Synuclein is a key protein in Parkinson's disease (PD) because it accumulates as fibrillar aggregates in pathologic hallmark features in affected brain regions, most notably in nigral dopaminergic neurons. Intraneuronal levels of this protein appear critical in mediating its toxicity, because multiplication of its gene locus leads to autosomal dominant PD, and transgenic animal models overexpressing human alpha-synuclein manifest impaired function or decreased survival of dopaminergic neurons. Here, we show that microRNA-7 (miR-7), which is expressed mainly in neurons, represses alpha-synuclein protein levels through the 3'-untranslated region (UTR) of alpha-synuclein mRNA. Importantly, miR-7-induced down-regulation of alpha-synuclein protects cells against oxidative stress. Further, in the MPTP-induced neurotoxin model of PD in cultured cells and in mice, miR-7 expression decreases, possibly contributing to increased alpha-synuclein expression. These findings provide a mechanism by which alpha-synuclein levels are regulated in neurons, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for PD and other alpha-synucleinopathies.
α-突触核蛋白是帕金森病（PD）中的关键蛋白，因为它在受影响脑区的病理标志性特征中以纤维状聚集体形式积累，最显著的是在黑质多巴胺能神经元中。这种蛋白的神经元内水平在介导其毒性方面似乎至关重要，因为其基因位点的倍增会导致常染色体显性PD，并且过表达人α-突触核蛋白的转基因动物模型表现出多巴胺能神经元功能受损或存活率降低。在此，我们表明主要在神经元中表达的微小RNA-7（miR-7）通过α-突触核蛋白mRNA的3'非翻译区（UTR）抑制α-突触核蛋白的蛋白水平。重要的是，miR-7诱导的α-突触核蛋白下调可保护细胞免受氧化应激。此外，在培养细胞和小鼠的MPTP诱导的PD神经毒素模型中，miR-7表达降低，这可能导致α-突触核蛋白表达增加。这些发现提供了一种在神经元中调节α-突触核蛋白水平的机制，对PD的发病机制具有启示意义，并提示miR-7作为PD和其他α-突触核蛋白病的治疗靶点。
