Measuring transcriptional dysregulation has been tremendously useful in a number of ways. First, the remarkable similarity between expression profiling changes between human HD brain and transgenic mice largely validates the utility of these valuable models in understanding transcriptional dysregulation in HD. Certain features of human HD, notably selective striatal neuronal death, are not well-replicated by transgenic mice expressing truncated forms of human huntingtin. These mice may thus be most useful for learning more about the transcriptional phenotype in HD. Expression profiling has also generated novel targets, molecules that were not previously suspected in HD pathogenesis, such as the cholesterol biosynthetic pathway and PGC-1α. The use of microarrays has already demonstrated potential as a therapeutic readout for clinical trials.
Important issues remain, however. Even though DNA microarray studies demonstrate a measure of selectivity in which genes are affected, it is clear that many genes are affected. Focusing on any single protein may therefore be a short-sighted strategy, and one ought to think of more upstream mechanisms.
The mechanisms producing these transcriptional signatures are largely unknown, although they certainly emanate from a single molecule: polyglutamine-expanded versions of the huntingtin protein. Several inroads have been advanced. Using a comparative approach Chen-Plotkin et al. found that downregulated genes have decreased binding of the transcription factor Sp1 to their promoters, compared to genes expressed at wild-type levels (Chen-Plotkin et al., 2006
). Similarly, at the promoters of susceptible genes, mutant Htt disrupts the assembly of transcriptional complexes (Zhai et al., 2005
). A systematic investigation of transcription factors and histone proteins will undoubtedly shed light on the causative mechanisms. Histones associated with downregulated genes are hypo-acetylated compared to histones associated with normally expressed genes (G. Sadri-Vakili and J.-H.J. Cha, unpublished data).
A looming issue is one of causality. While altered transcription is clearly a phenotype, it is not clear if these gene changes are causative or epiphenomenal. The critical test will be to see if correcting this abnormal phenotype produces clinical benefit. In this regard, recent experience with HDAC inhibitors has been instructive (reviewed in Sadri-Vakili and Cha, 2006
). Transgenic HD mice are improved when treated with HDAC inhibitors (Ferrante et al., 2003
; Gardian et al., 2005
; Hockly et al., 2003
), and some of these compounds are now being tested in human HD patients.
Overall, transcriptional signatures illustrate the cycles of discovery in Huntington's disease, in which initial observation from postmortem human brain informs preliminary experiments in animal and cellular models. Additional insights developed in these models, fueled by biotechnological innovation such as the development of DNA microarrays, can then be brought to bear on the human patient. The ultimate progress of this cycle will be measured not only in new ideas and new targets but, ultimately, in new therapies.