Department of Pharmacological Sciences and Centre for Stem Cell Research, Università degli Studi di Milano, Milan, Italy.
Physiol Rev. 2010 Jul;90(3):905-81. doi: 10.1152/physrev.00041.2009.
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding for huntingtin protein. A lot has been learned about this disease since its first description in 1872 and the identification of its causative gene and mutation in 1993. We now know that the disease is characterized by several molecular and cellular abnormalities whose precise timing and relative roles in pathogenesis have yet to be understood. HD is triggered by the mutant protein, and both gain-of-function (of the mutant protein) and loss-of-function (of the normal protein) mechanisms are involved. Here we review the data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution. We focus on the known functions of wild-type huntingtin that are fundamental for the survival and functioning of the brain neurons that predominantly degenerate in HD. We summarize data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive. We also review the different mechanisms by which the mutation in huntingtin causes toxicity. This may arise both from cell-autonomous processes and dysfunction of neuronal circuitries. We then focus on novel therapeutical targets and pathways and on the attractive option to counteract HD at its primary source, i.e., by blocking the production of the mutant protein. Strategies and technologies used to screen for candidate HD biomarkers and their potential application are presented. Furthermore, we discuss the opportunities offered by intracerebral cell transplantation and the likely need for these multiple routes into therapies to converge at some point as, ideally, one would wish to stop the disease process and, at the same time, possibly replace the damaged neurons.
亨廷顿病（HD）是一种神经退行性疾病，由编码亨廷顿蛋白的基因中的 CAG 重复扩展引起。自 1872 年首次描述该病以来，以及 1993 年确定其致病基因和突变以来，我们已经对该病有了很多了解。我们现在知道，该疾病的特征是存在几种分子和细胞异常，但其确切发病时间和相对作用仍有待了解。HD 是由突变蛋白触发的，涉及获得功能（突变蛋白）和丧失功能（正常蛋白）机制。在这里，我们回顾了描述在过去 8 亿年的进化过程中古老的亨廷顿基因和多聚谷氨酰胺特征出现的数据。我们重点介绍野生型亨廷顿蛋白的已知功能，这些功能对在 HD 中主要退化的脑神经元的生存和功能至关重要。我们总结了表明这些有益活性丧失如何降低这些神经元存活能力的数据。我们还回顾了亨廷顿突变导致毒性的不同机制。这可能既来自细胞自主过程，也来自神经元回路的功能障碍。然后，我们专注于新的治疗靶标和途径，并探讨了在其主要来源处拮抗 HD 的诱人选择，即通过阻止突变蛋白的产生。介绍了用于筛选候选 HD 生物标志物的策略和技术及其潜在应用。此外，我们讨论了脑内细胞移植提供的机会，以及这些进入治疗的多种途径在某个时候汇聚的可能性，因为理想情况下，人们希望停止疾病进程，同时可能取代受损的神经元。
