Kocerha Jannet, Xu Yan, Prucha Melinda S, Zhao Dongming, Chan Anthony W S
Division of Neuropharmacology and Neurologic Disease, Yerkes National Primate Research Center, 954 Gatewood Rd,, N,E Atlanta, GA 30329, USA.
Mol Brain. 2014 Jun 13;7:46. doi: 10.1186/1756-6606-7-46.
Huntington's Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene. MicroRNAs (miRNAs) have recently been implicated as epigenetic regulators of neurological disorders, however, their role in HD pathogenesis is not well defined. Here we study transgenic HD monkeys (HD monkeys) to examine miRNA dysregulation in a primate model of the disease.
In this report, 11 miRNAs were found to be significantly associated (P value < 0.05) with HD in the frontal cortex of the HD monkeys. We further focused on one of those candidates, miR-128a, due to the corresponding disruption in humans and mice with HD as well as its intriguing lists of gene targets. miR-128a was downregulated in our HD monkey model by the time of birth. We then confirmed that miR-128a was also downregulated in the brains of pre-symptomatic and post-symptomatic HD patients. Additionally, our studies confirmed a panel of canonical HD signaling genes regulated by miR-128a, including HTT and Huntingtin Interaction Protein 1 (HIP1).
Our studies found that miR-128a may play a critical role in HD and could be a viable candidate as a therapeutic or biomarker of the disease.
亨廷顿舞蹈症（HD）是一种进行性神经退行性疾病，由亨廷顿蛋白（HTT）基因中的单一致病突变引起。微小RNA（miRNA）最近被认为是神经系统疾病的表观遗传调节因子，然而，它们在HD发病机制中的作用尚不清楚。在此，我们研究转基因HD猴（HD猴），以检查该疾病灵长类动物模型中的miRNA失调情况。
在本报告中，发现11种miRNA与HD猴额叶皮质中的HD显著相关（P值<0.05）。由于HD患者和HD小鼠中相应的破坏以及其有趣的基因靶标列表，我们进一步关注其中一个候选物miR-128a。在我们的HD猴模型中，miR-128a在出生时就被下调。然后我们证实，miR-128a在症状前和症状后HD患者的大脑中也被下调。此外，我们的研究证实了一组受miR-128a调节的经典HD信号基因，包括HTT和亨廷顿相互作用蛋白1（HIP1）。
我们的研究发现，miR-128a可能在HD中起关键作用，并且可能是该疾病治疗或生物标志物的可行候选物。
