MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK
Int Rev Neurobiol. 2011;98:373-418. doi: 10.1016/B978-0-12-381328-2.00015-8.
Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder presenting in midlife. Multiple pathogenic mechanisms which hypothesise how the expanded CAG repeat causes manifest disease have been suggested since the mutation was first detected. These mechanisms include events that operate at both the gene and protein levels. It has been proposed that somatic instability of the CAG repeat could underlie the striatal-specific pathology observed in HD, although how this occurs and what consequences this has in the disease state remain unknown. The form in which the Htt protein exists within the cell has been extensively studied in terms of both its role in aggregate formation and its cellular processing. Protein-protein interactions, post-translational modifications and protein cleavage have all been suggested to contribute to HD pathogenesis. The potential downstream effects of the mutant Htt protein are also noted here. In particular, the adverse effect of the mutant Htt protein on cellular protein degradation, subcellular transport and transcription are explored, and its role in energy metabolism and excitotoxicity investigated. Elucidating the mechanisms at work in HD pathogenesis and determining when they occur in relation to disease is an important step in the pathway to therapeutic interventions.
亨廷顿病（HD）是一种常染色体显性遗传、进行性神经退行性疾病，中年发病。自该突变首次被发现以来，人们提出了多种假设性的致病机制，以解释扩张的 CAG 重复序列如何导致疾病的发生。这些机制包括在基因和蛋白质水平上发生的事件。有人提出，CAG 重复的体细胞不稳定性可能是 HD 中观察到的纹状体特异性病理学的基础，尽管这种情况是如何发生的以及它在疾病状态下有什么后果仍不清楚。Htt 蛋白在细胞内的存在形式已在聚集形成及其细胞加工方面进行了广泛研究。蛋白-蛋白相互作用、翻译后修饰和蛋白切割都被认为有助于 HD 的发病机制。这里还提到了突变型 Htt 蛋白的潜在下游效应。特别探讨了突变型 Htt 蛋白对细胞蛋白降解、亚细胞转运和转录的不良影响，以及其在能量代谢和兴奋性毒性中的作用。阐明 HD 发病机制中的作用机制，并确定它们与疾病相关的发生时间，是治疗干预途径中的重要步骤。
