Ho L W, Carmichael J, Swartz J, Wyttenbach A, Rankin J, Rubinsztein D C
Department of Medical Genetics, Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, Cambridge Institute of Medical Research, Addenbrooke's Hospital.
Psychol Med. 2001 Jan;31(1):3-14. doi: 10.1017/s0033291799002871.
Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).
This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts.
Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis.
Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.
亨廷顿舞蹈症（HD）是一种具有常染色体显性遗传模式的致命性神经退行性疾病。它会导致进行性痴呆、精神症状以及使人丧失能力的舞蹈样运动障碍，最终导致过早死亡。HD是由一个编码功能未知蛋白质（称为亨廷顿蛋白）的基因中CAG重复序列数量增加所致。三核苷酸CAG编码氨基酸谷氨酰胺，而扩展的CAG重复序列被翻译成一系列不间断的谷氨酰胺残基（一个多聚谷氨酰胺序列）。
本综述描述了HD的流行病学、临床症状学、神经病理学特征和遗传学。主要目的是研究动物和细胞模型的重要发现，并评估它们如何丰富了我们对HD以及其他由扩展的多聚谷氨酰胺序列引起的疾病发病机制的理解。
纹状体和皮质神经元发生选择性死亡。HD突变可能赋予该蛋白质有害的功能获得。在HD患者和转基因小鼠模型中出现了含有亨廷顿蛋白和泛素的神经元核内包涵体。其他提出的导致神经病理学的机制包括兴奋性毒性、氧化应激、能量代谢受损、异常的蛋白质相互作用和细胞凋亡。
尽管对HD和其他多聚谷氨酰胺疾病的研究积累了许多有趣的发现，但关于核内包涵体和蛋白质聚集体的确切作用、选择性神经元死亡机制以及疾病延迟发作等仍有许多未解决的问题。这些领域的进一步知识将推动新型治疗策略的发展。
