Wright Dean J, Renoir Thibault, Gray Laura J, Hannan Anthony J
Faculty of Health, School of Medicine, Deakin University, Locked Bag 20000, Geelong, VIC, 3220, Australia.
Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, VIC, 3010, Australia.
Adv Neurobiol. 2017;15:93-128. doi: 10.1007/978-3-319-57193-5_4.
Huntington's disease (HD) is a tandem repeat disorder involving neurodegeneration and a complex combination of symptoms. These include psychiatric symptoms, cognitive deficits culminating in dementia, and the movement disorder epitomised by motor signs such as chorea. HD is caused by a CAG repeat expansion encoding an extended tract of the amino acid glutamine in the huntingtin protein. This polyglutamine expansion appears to induce a 'change of function', possibly a 'gain of function', in the huntingtin protein, which leads to various molecular and cellular cascades of pathogenesis. In the current review, we will briefly describe these broader aspects of HD pathogenesis, but will then focus on specific aspects where there are substantial bodies of experimental evidence, including oxidative stress, mitochondrial dysfunction, glutamatergic dysfunction and neuroinflammation. Furthermore, we will review recent preclinical therapeutic approaches targeting some of these pathogenic pathways, their clinical implications and future directions.
亨廷顿舞蹈症（HD）是一种串联重复序列疾病，涉及神经退行性变以及一系列复杂的症状。这些症状包括精神症状、最终发展为痴呆的认知缺陷，以及以舞蹈症等运动体征为代表的运动障碍。HD是由CAG重复序列扩增引起的，该扩增导致亨廷顿蛋白中编码一段延长的谷氨酰胺氨基酸序列。这种聚谷氨酰胺扩增似乎会诱导亨廷顿蛋白发生“功能改变”，可能是“功能获得”，进而引发各种分子和细胞层面的致病级联反应。在本综述中，我们将简要描述HD发病机制的这些更广泛的方面，但随后将重点关注有大量实验证据支持的特定方面，包括氧化应激、线粒体功能障碍、谷氨酸能功能障碍和神经炎症。此外，我们将综述针对其中一些致病途径的近期临床前治疗方法、它们的临床意义及未来方向。
