Transcriptional signatures in Huntington's disease

Abstract

While selective neuronal death has been an influential theme in Huntington's disease (HD), there is now a preponderance of evidence that significant neuronal dysfunction precedes frank neuronal death. The best evidence for neuronal dysfunction is the observation that gene expression is altered in HD brain, suggesting that transcriptional dysregulation is a central mechanism. Studies of altered gene expression began with careful observations of postmortem human HD brain and subsequently were accelerated by the development of transgenic mouse models. The application of DNA microarray technology has spurred tremendous progress with respect to the altered transcriptional processes that occur in HD, through gene expression studies of both transgenic mouse models as well as cellular models of HD. Gene expression profiles are remarkably comparable across these models, bolstering the idea that transcriptional signatures reflect an essential feature of disease pathogenesis. Finally, gene expression studies have been applied to human HD, thus not only validating the approach of using model systems, but also solidifying the idea that altered transcription is a key mechanism in HD pathogenesis. In the future, gene expression profiling will be used as a readout in clinical trials aimed at correcting transcriptional dysregulation in Huntington's disease.

Introduction

The ‘cycle of discovery’ is well-demonstrated in considering Huntington's disease (Wexler et al., 1991). In this cycle, fundamental observations about a disease are made in human patients. These clinical and pathologic observations form the foundation from which scientific hypotheses can be constructed. These hypotheses in turn lead to identification of defective genes or environmental causes, development of animal models, and preclinical testing. In vitro models, particularly those involving cell biology, as well as transgenic animal models provide additional insight into mechanisms of disease pathogenesis. The cycle is completed when these advances are brought to bear upon the initial human malady. In the example of Huntington's disease, fundamental observations including field studies in Venezuela led ultimately to the discovery of the HD gene in 1993 (Huntington's Disease Collaborative Research Group, 1993). Discovery of the molecular defect then led to the development of transgenic HD mice, followed subsequently by model systems including yeast, Drosophila, C. elegans, and transgenic rats. Preclinical therapeutics which have been screened on transgenic animal models have now been introduced into human clinical trials, thus completing the cycle of discovery.

The idea of transcriptional dysregulation in Huntington's disease thus follows a similar trajectory. Starting from initial observations in postmortem human HD brain, subsequent observations were first confirmed and then expanded in transgenic mouse models, and finally, the human HD brain has been re-interrogated. Along the way, we have gained significant perspective on how the mutant form of the huntingtin (Htt) protein causes selective neuronal death in the brain. In addition, these transcriptional studies have fundamentally revolutionized our view of the role of normal huntingtin. These steps through the cycle of discovery confirm that transcriptional dysregulation is a key central feature of HD pathogenesis, and may therefore serve as a target for rational therapy. In this review, I focus on the transcriptional signatures, those studies that have detailed the alteration of mRNA expression in Huntington's disease.