Protein Interactions and Target Discovery in Huntington's Disease

Abstract

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 Caenorhabditis elegans and Drosophila (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 in vitro 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.