Fukuoka Masashi, Takahashi Masaki, Fujita Hiromi, Chiyo Tomoko, Popiel H Akiko, Watanabe Shoko, Furuya Hirokazu, Murata Miho, Wada Keiji, Okada Takashi, Nagai Yoshitaka, Hohjoh Hirohiko
Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, Japan; Division of RNA Medical Science, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Mol Ther Nucleic Acids. 2018 Jun 1;11:79-90. doi: 10.1016/j.omtn.2018.01.007. Epub 2018 Feb 2.
Huntington's disease (HD) is an intractable neurodegenerative disorder caused by mutant Huntingtin (HTT) proteins that adversely affect various biomolecules and genes. MicroRNAs (miRNAs), which are functional small non-coding RNAs, are also affected by mutant HTT proteins. Here, we show amelioration in motor function and lifespan of HD-model mice, R6/2 mice, by supplying miR-132 to HD brains using a recombinant adeno-associated virus (rAAV) miRNA expression system. miR-132 is an miRNA related to neuronal maturation and function, but the level of miR-132 in the brain of R6/2 mice was significantly lower than that of wild-type mice. Our miR-132 supplemental treatment, i.e., supplying miR-132 to the brain, produced symptomatic improvement or retarded disease progression in R6/2 mice; interestingly, it had little effect on disease-causing mutant HTT mRNA expression and its products. Therefore, the findings suggest that there may be a therapeutic way to treat HD without inhibiting and/or repairing disease-causing HTT genes and gene products. Although miR-132 supplement may not be a definitive treatment for HD, it may become a therapeutic method for relieving HD symptoms and delaying HD progression.
亨廷顿舞蹈症（HD）是一种由突变的亨廷顿蛋白（HTT）引起的难治性神经退行性疾病，突变的HTT蛋白会对各种生物分子和基因产生不利影响。微小RNA（miRNA）是具有功能的小型非编码RNA，也会受到突变HTT蛋白的影响。在这里，我们使用重组腺相关病毒（rAAV）miRNA表达系统向HD小鼠模型R6/2小鼠的大脑中提供miR-132，结果显示其运动功能和寿命得到改善。miR-132是一种与神经元成熟和功能相关的miRNA，但R6/2小鼠大脑中miR-132的水平明显低于野生型小鼠。我们的miR-132补充治疗，即向大脑中提供miR-132，使R6/2小鼠的症状得到改善或延缓了疾病进展；有趣的是，它对致病突变HTT mRNA表达及其产物几乎没有影响。因此，这些发现表明，可能存在一种不抑制和/或修复致病HTT基因及其产物的治疗HD的方法。虽然补充miR-132可能不是治疗HD的最终方法，但它可能成为缓解HD症状和延缓HD进展的一种治疗方法。
