Reddy P Hemachandra, Mao Peizhong, Manczak Maria
Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, West Campus, Oregon Health and Science University, Beaverton, OR 97006, USA.
Brain Res Rev. 2009 Jun;61(1):33-48. doi: 10.1016/j.brainresrev.2009.04.001. Epub 2009 Apr 24.
Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder, characterized by chorea, involuntary movements, and cognitive impairments. Tremendous progress has been made since the discovery of HD gene in 1993, in terms of developing animal models to study the disease process, unraveling the expression and function of wild-type and mutant huntingtin (Htt) proteins in the central and peripheral nervous systems, and understanding expanded CAG repeat containing mutant Htt protein interactions with CNS proteins in the disease process. HD progression has been found to involve several pathomechanisms, including expanded CAG repeat protein interaction with other CNS proteins, transcriptional dysregulation, calcium dyshomeostasis, abnormal vesicle trafficking, and defective mitochondrial bioenergetics. Recent studies have found that mutant Htt is associated with mitochondria and causes mitochondrial structural changes, decreases mitochondrial trafficking, and impairs mitochondrial dynamics in the neurons affected by HD. This article discusses recent developments in HD research, with a particular focus on intracellular and intramitochondrial calcium influx, mitochondrial DNA defects, and mitochondrial structural and functional abnormalities in HD development and progression. Further, this article outlines the current status of mitochondrial therapeutics with a special reference to Dimebon.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的神经退行性疾病，其特征为舞蹈症、不自主运动和认知障碍。自1993年发现HD基因以来，在开发用于研究疾病进程的动物模型、阐明野生型和突变型亨廷顿蛋白（Htt）在中枢和外周神经系统中的表达及功能，以及了解含扩展CAG重复序列的突变型Htt蛋白在疾病进程中与中枢神经系统蛋白的相互作用等方面均取得了巨大进展。已发现HD的进展涉及多种病理机制，包括扩展的CAG重复序列蛋白与其他中枢神经系统蛋白的相互作用、转录失调、钙稳态失衡、异常囊泡运输以及线粒体生物能量学缺陷。最近的研究发现，突变型Htt与线粒体相关，并导致线粒体结构改变，减少线粒体运输，并损害受HD影响的神经元中的线粒体动力学。本文讨论了HD研究的最新进展，特别关注细胞内和线粒体内钙内流、线粒体DNA缺陷以及HD发生和进展过程中的线粒体结构和功能异常。此外，本文概述了线粒体治疗的现状，并特别提及了Dimebon。
