Department of Human Genetics, Ruhr-University Bochum, Germany.
Mol Neurodegener. 2011 May 19;6(1):32. doi: 10.1186/1750-1326-6-32.
Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.
In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.
These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.
亨廷顿病（HD）是一种遗传性神经退行性疾病，由亨廷顿 HTT（HD）基因中的 CAG 重复异常扩展引起。发病年龄（AO）的主要遗传决定因素是 HTT CAG 重复的长度；然而，HD 的 AO 遗传贡献的其余部分在很大程度上尚未阐明。最近的研究表明，过氧化物酶体增殖物激活受体γ共激活因子 1a（PGC-1α）的功能障碍导致线粒体功能障碍，并似乎在 HD 发病机制中发挥重要作用。进一步的遗传证据表明 PGC-1α 参与了 HD 的发病机制，这是因为发现编码 PGC-1α 的 PPARGC1A 基因中的序列变异对 HD 的 AO 具有修饰作用。在这项研究中，我们假设 PGC-1α 下游靶标的多态性也可能导致 AO 的变化。
在超过 400 名德国 HD 患者中，核呼吸因子 1 基因 NRF-1 和由 TFAM 编码的线粒体转录因子 A 的多态性与 HD 的 AO 呈名义显著相关。当将这些结果与先前描述的修饰因子 rs7665116 在 PPARGC1A 中的作用以及 CO1 中的 C7028T（线粒体 haplogroup H）结合在多变量模型中时，AO 变化的大部分可以由显著修饰因子及其相互作用的联合效应来解释。
这些结果强调了线粒体功能的损害在 HD 的发病机制中起着关键作用，并且 PGC-1α 的上游转录激活因子可能是治疗 HD 的有用靶点。
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