PDF(Pubmed)
Abstract：
The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease-modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.
摘要：
亨廷顿病（HD）的致病突变，亨廷顿基因（HTT）第一个外显子中扩展的三核苷酸重复序列是天然多态性的，并且不可避免地与39CAG重复以上的疾病症状相关。尽管HD的对症药物治疗可以改善受影响患者的运动和非运动症状，这些药物不能阻止正在进行的神经变性和疾病的进展，导致严重的运动和认知障碍和死亡。迄今为止,仍然迫切需要开发有效的疾病改善疗法来减缓甚至阻止HD的进展.直接干预疾病根源的能力日益增强，即HTT转录和其mRNA的翻译，因此有必要尽可能准确地了解HD的发病机制。除了长期假定的多谷氨酰胺扩增的突变HTT蛋白的毒性外，越来越多的证据表明,含CAG重复序列的RNA也可能直接参与毒性.最近的研究已经确定了顺式(DNA修复基因)和反式(CAA中断的丢失/重复)作用变体作为发病年龄(AO)和疾病进展的主要调节剂。越来越广泛的数据表明，躯体不稳定作为AO的驱动因素以及疾病进展和严重程度，不仅在HD中，而且在其他多聚谷氨酰胺疾病中。因此，重复DNA序列的体细胞扩增对于促进各自的重复长度达到导致三核苷酸疾病的明显神经退行性症状的阈值可能是必不可少的。这些发现支持体细胞扩张作为HD和相关重复扩张障碍的潜在治疗靶标。
