Miller John P., Hughes Robert E.
Huntington’s disease (HD) is a devastating neurological disorder for which we currently have no effective treatments. Although patients are typically treated with drugs that can modify symptoms, none of these current drug regimens are thought to modify the onset, progress, or ultimate fatality of HD. A major step forward in terms of understanding the mechanism underlying HD and thus toward developing rational approaches to drug development occurred in 1993 with the cloning of the HD gene (Willard, 1993). From a drug development perspective, one great outcome of this advancement was to create the ability to express the mutant HD gene in cell-based and transgenic models that can experimentally recapitulate aspects of HD pathology (see Chapters 5, 6, and 7, this volume). Such assays are invaluable tools for characterizing pathogenic mechanisms and discovering targets and small molecule modifiers of toxicity mediated by mutant Htt expression. The identification of the protein also allows us to determine its interacting partners and thereby place the pathogenesis of the disease in a proteomic context. However, despite early enthusiasm suggesting that the discovery of the precise genetic cause of HD could provide a fast track to an effective treatment, disease-modifying small molecule interventions for HD remain to be fully developed. Target discovery and target validation are key early steps in the drug discovery process (see Chapter 4, this volume). There are a number of approaches to target discovery that include nomination and testing of candidate targets based on consideration of biological and molecular features of specific diseases. Candidate targets can also be inferred from genetic modifier screens in model organisms such as and (see Chapter 6, this volume). More recently, high-throughput RNA interference (RNAi) screening in cell-based models of disease has provided an opportunity to use unbiased genome-wide screens to identify potential targets capable of modifying models of disease phenotypes (Cronin et al., 2009; Krishnan et al., 2008; Luo et al., 2009). Candidate genes identified through RNAi-mediated phenotypes can be further validated in higher content models, such as crossing transgenic HD mice with a strain that bears a genetic modification of a candidate target. Another powerful method for target identification is the use of protein interaction studies. This chapter will focus on the role of protein interactions in HD and specifically on how knowledge of protein interaction networks can inform target discovery and validation processes for HD drug development.
亨廷顿舞蹈症（HD）是一种极具破坏性的神经疾病，目前我们尚无有效的治疗方法。尽管患者通常会接受能够改善症状的药物治疗，但目前这些药物疗法均无法改变HD的发病、进展或最终致死情况。1993年HD基因的克隆在理解HD潜在机制以及朝着开发合理的药物研发方法方面迈出了重要一步（威拉德，1993年）。从药物研发的角度来看，这一进展的一个重大成果是能够在基于细胞的模型和转基因模型中表达突变的HD基因，这些模型能够通过实验重现HD病理学的各个方面（见本卷第5、6和7章）。此类检测对于表征致病机制以及发现由突变型亨廷顿蛋白（Htt）表达介导的毒性的靶点和小分子调节剂而言是非常宝贵的工具。该蛋白的鉴定还使我们能够确定其相互作用伙伴，从而将疾病的发病机制置于蛋白质组学背景中。然而，尽管早期人们满怀热情，认为发现HD的确切遗传病因可以为有效治疗提供一条捷径，但针对HD的疾病修饰性小分子干预措施仍有待充分开发。靶点发现和靶点验证是药物研发过程中的关键早期步骤（见本卷第4章）。有多种靶点发现方法，包括基于对特定疾病的生物学和分子特征的考虑来提名和测试候选靶点。候选靶点也可以从诸如 和 等模式生物的遗传修饰筛选中推断出来（见本卷第6章）。最近，在基于细胞的疾病模型中进行的高通量RNA干扰（RNAi）筛选提供了一个机会，可利用无偏倚的全基因组筛选来识别能够改变疾病表型模型的潜在靶点（克罗宁等人，2009年；克里希南等人，2008年；罗等人，2009年）。通过RNAi介导的表型鉴定出的候选基因可以在更高内涵的模型中进一步验证，例如将转基因HD小鼠与携带候选靶点基因修饰的品系杂交。另一种强大的靶点鉴定方法是利用蛋白质相互作用研究。本章将重点关注蛋白质相互作用在HD中的作用，特别是蛋白质相互作用网络的知识如何为HD药物研发的靶点发现和验证过程提供信息。
