Kumar Lalit, Nazir Aamir
Laboratory of Functional Genomics and Molecular Toxicology, Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow, India.
Front Mol Neurosci. 2017 Oct 13;10:328. doi: 10.3389/fnmol.2017.00328. eCollection 2017.
Neurodegenerative Parkinson's disease (PD) is a multi-factorial disorder lacking complete cure. Understanding the complete mechanism of initiation and progression of this disease has been quite challenging; however, progress has been made toward deciphering certain genetic aspects related to the disease condition. Genetics studies have provided clues toward the role of microRNAs (miRNAs) in various disease conditions. One of the crucial miRNA molecules, let-7, is highly conserved miRNA and is known to regulate important functions of development and viability; its altered expression has been reported in model of PD. We carried out studies with let-7, employing transgenic model expressing 'human' alpha-synuclein and developed a let-7 loss-of-function model toward studying the downstream effects related to PD. We observed that let-7 miRNA was upregulated in model of PD and figured that loss of let-7 miRNA leads to decreased alpha-synuclein expression, increased autophagy, increased Daf-16 expression, increased oxidative stress and increased lipid content with no effect on dopaminergic/acetylcholinergic neurons. Our findings indicate that let-7 miRNA regulates PD-associated pathways. Our study provides insight toward the role of let-7 in regulating expression of genes associated with these pathways which might have implications on the multi-factorial nature of PD. Potential pharmacological agents modulating the expression of let-7 could be studied toward targeting the multi-factorial aspect of PD.
神经退行性帕金森病（PD）是一种缺乏完全治愈方法的多因素疾病。了解这种疾病发生和进展的完整机制极具挑战性；然而，在解读与疾病状况相关的某些遗传方面已经取得了进展。遗传学研究为微小RNA（miRNA）在各种疾病状况中的作用提供了线索。关键的miRNA分子之一，即let-7，是一种高度保守的miRNA，已知其可调节发育和生存能力的重要功能；在帕金森病模型中已报道其表达发生改变。我们利用表达“人”α-突触核蛋白的转基因模型对let-7进行了研究，并建立了一个let-7功能丧失模型来研究与帕金森病相关的下游效应。我们观察。我们观察到在帕金森病模型中let-7 miRNA上调，并发现let-7 miRNA的缺失导致α-突触核蛋白表达降低、自噬增加、Daf-16表达增加、氧化应激增加和脂质含量增加，而对多巴胺能/乙酰胆碱能神经元没有影响。我们的研究结果表明let-7 miRNA调节与帕金森病相关的信号通路。我们的研究为let-7在调节与这些信号通路相关的基因表达中的作用提供了见解，这可能对帕金森病的多因素性质具有重要意义。可以研究调节let-7表达的潜在药物制剂，以针对帕金森病的多因素方面。
