Laboratory of Molecular and Behavioral Neurobiology, Health Sciences Center, Federal University of Espirito Santo, Vitória, ES, Brazil.
Graduate Program in Neuroscience, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
J Mol Neurosci. 2017 Dec;63(3-4):342-348. doi: 10.1007/s12031-017-0984-z. Epub 2017 Oct 10.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive deficits, and psychiatric symptoms. The primary genetic cause is an expansion of cytosine adenine guanine (CAG) nucleotides of the huntingtin gene, which codes an important protein involved with neuronal signaling. The severity of HD correlates with the number of CAG repeats and individuals with longer expansions have an earlier onset and more severe symptoms. A microarray study conducted by our research group showed alteration in DNAH6 gene (encoding dynein axonemal heavy chain 6). DNAH6 belongs to dynein family, whose members are constituents of the microtubule-associated motor proteins and is downregulated in the striatum of a HD mouse model (knockin Hdh). In this manner, our goal was to confirm these downregulations in the mouse model and verify if the same alteration in the axonemal DNAH6 gene expression is observed in blood samples of HD patients. Blood samples were collected from 17 patients with clinical diagnosis of HD and 12 healthy individuals and RNA extracted for qPCR analysis. Microarray data were confirmed by qPCR in knockin Hdh, and DNAH6 was severely decreased in those mice, as compared to control mice (Hdh). Notably, decreased expression of DNAH6 gene was also observed in HD patients when compared to control group and negatively correlates with the CAG expansion. Although further studies are necessary to underlie the molecular mechanisms of dynein-htt interaction, this data highlights DNAH6 as a potential new blood marker for HD.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，其特征是运动功能障碍、认知缺陷和精神症状。主要的遗传原因是亨廷顿基因中胞嘧啶腺嘌呤鸟嘌呤（CAG）核苷酸的扩展，该基因编码一种与神经元信号传导有关的重要蛋白质。HD 的严重程度与 CAG 重复数相关，具有较长扩展的个体发病较早，症状更严重。我们的研究小组进行的微阵列研究显示 DNAH6 基因（编码轴丝动力蛋白重链 6）发生改变。DNAH6 属于动力蛋白家族，其成员是微管相关运动蛋白的组成部分，在 HD 小鼠模型（knockin Hdh）的纹状体中下调。因此，我们的目标是在小鼠模型中证实这些下调，并验证 HD 患者的血液样本中是否观察到轴丝 DNAH6 基因表达的相同改变。从 17 名临床诊断为 HD 的患者和 12 名健康个体中采集血液样本，并提取 RNA 进行 qPCR 分析。微阵列数据在 knockin Hdh 中得到 qPCR 的证实，与对照小鼠（Hdh）相比，这些小鼠中的 DNAH6 表达严重降低。值得注意的是，与对照组相比，HD 患者的 DNAH6 基因表达也降低，与 CAG 扩展呈负相关。尽管需要进一步研究来阐明动力蛋白-htt 相互作用的分子机制，但这些数据突出了 DNAH6 作为 HD 的潜在新血液标志物。
