Martinez Bridget, Peplow Philip V
Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM, USA; Department of Medicine, St. Georges University School of Medicine, Grenada.
Department of Anatomy, University of Otago, Dunedin, New Zealand.
Neural Regen Res. 2021 Nov;16(11):2159-2169. doi: 10.4103/1673-5374.310673.
A review of recent animal models of Huntington's disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex, and which were mostly downregulated. Among the altered microRNAs were miR-9/9*, miR-29b, miR-124a, miR-132, miR-128, miR-139, miR-122, miR-138, miR-23b, miR-135b, miR-181 (all downregulated) and miR-448 (upregulated), and similar changes had been previously found in Huntington's disease patients. In the animal cell studies, the altered microRNAs included miR-9, miR-9*, miR-135b, miR-222 (all downregulated) and miR-214 (upregulated). In the animal models, overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level, lowered the mutant huntingtin aggregates in striatum and cortex, and improved performance in behavioral tests. Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124. In the animal cell models, overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin -enriched foci of ≥ 2 µm. Also, overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid. Exogenous expression of miR-214, miR-146a, miR-150, and miR-125b decreased endogenous expression of huntingtin mRNA and protein in Hdh/Hdh cells. Further studies with animal models of Huntington's disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington's disease in patients and slowing its progression.
对近期亨廷顿舞蹈症动物模型的一项综述显示，许多微小RNA在纹状体和大脑皮层中的表达水平发生了改变，且大多呈下调状态。在这些发生改变的微小RNA中，有miR-9/9*、miR-29b、miR-124a、miR-132、miR-128、miR-139、miR-122、miR-138、miR-23b、miR-135b、miR-181（均下调）以及miR-448（上调），并且此前在亨廷顿舞蹈症患者中也发现了类似变化。在动物细胞研究中，发生改变的微小RNA包括miR-9、miR-9*、miR-135b、miR-222（均下调）以及miR-214（上调）。在动物模型中，miR-155和miR-196a的过表达导致突变型亨廷顿蛋白的mRNA和蛋白水平降低，减少了纹状体和皮层中突变型亨廷顿蛋白的聚集体，并改善了行为测试中的表现。miR-132和miR-124的过表达也使行为测试中的表现得到改善。在动物细胞模型中，miR-22的过表达提高了感染突变型亨廷顿蛋白的大鼠原代皮层和纹状体神经元的活力，并减少了≥2 µm的富含亨廷顿蛋白的病灶。此外，miR-22的过表达增强了用3-硝基丙酸处理的大鼠原代纹状体神经元的存活率。miR-214、miR-146a、miR-150和miR-125b的外源表达降低了Hdh/Hdh细胞中亨廷顿蛋白mRNA和蛋白的内源性表达。有必要对亨廷顿舞蹈症动物模型进行进一步研究，以验证这些发现，并确定那些过表达能够抑制突变型亨廷顿蛋白产生及其他有害过程的特定微小RNA，这可能为治疗亨廷顿舞蹈症患者并减缓其病程提供更有效的方法。
