Illarioshkin S N, Klyushnikov S A, Vigont V A, Seliverstov Yu A, Kaznacheyeva E V
Research Center of Neurology, Moscow, 125367, Russia.
Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
Biochemistry (Mosc). 2018 Sep;83(9):1030-1039. doi: 10.1134/S0006297918090043.
Huntington's disease (HD) is a severe autosomal dominant neurodegenerative disorder characterized by a combination of motor, cognitive, and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex, and inevitably progressive course resulting in death 5-20 years after manifestation of its symptoms. HD is caused by expansion of CAG repeats in the HTT gene, which leads to pathological elongation of the polyglutamine tract within the respective protein - huntingtin. In this review, we present a modern view on molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. Main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as systemic failure of transcription, mitochondrial dysfunction and suppression of energy metabolism, abnormalities of cytoskeleton and axonal transport, microglial inflammation, decrease in synthesis of brain-derived neurotrophic factor, etc.
亨廷顿舞蹈症（HD）是一种严重的常染色体显性神经退行性疾病，其特征为运动、认知和精神症状的综合表现，基底神经节和大脑皮层萎缩，以及症状出现后5至20年不可避免的进行性病程，最终导致死亡。HD由HTT基因中CAG重复序列的扩增引起，这导致相应蛋白质——亨廷顿蛋白内聚谷氨酰胺链的病理性延长。在本综述中，我们阐述了对HD分子生物学的现代观点，HD作为聚谷氨酰胺疾病组的代表，重点关注突变亨廷顿蛋白的构象变化、其细胞加工过程中的紊乱以及退化神经元中的蛋白水解应激。详细讨论了HD神经退行性变的主要发病机制，如转录系统故障、线粒体功能障碍和能量代谢抑制、细胞骨架和轴突运输异常、小胶质细胞炎症、脑源性神经营养因子合成减少等。
