Transcriptional dysregulation and neuronal dysfunction

In 1993, the isolation of the gene (HD) responsible for Huntington's disease offered hope for understanding the molecular basis of this dreadful neurodegenerative disease. But, the amino acid sequence of the encoded protein, huntingtin, offered few clues to its function, and expression of HD appeared to be ubiquitous, rather than limited to the central nervous system. Instead, the key to Huntington's disease seemed to lie in the sequence of HD alleles: all disease alleles include a CAG trinucleotide repeat expansion, encoding a polyglutamine (polyQ) tract within the mature protein. CAG repeat expansions have now been identified in seven other genes, all associated with fatal neurodegenerative diseases.Expanded polyQ tracts form insoluble aggregates resembling amyloid fibrils and can cause neurotoxic effects in divergent organisms, independent of protein context. But what are the cellular targets of polyQ, and how does this sequence cause neuronal dysfunction? An early clue was that polyQ-rich sequences are common among transcription factors. Furthermore, polyQ tracts interact directly with components of the transcriptional machinery, including factors involved in histone modification. In recent studies using mouse models, proteins with expanded polyQ tracts induced transcriptional dysregulation before the onset of neurological symptoms, suggesting a cause-and-effect relationship. Moreover, many of the affected genes are relevant to neuronal function. Could transcriptional dysregulation cause polyQ pathogenesis?To examine whether expanded polyQ tracts interfere with gene expression, Hughes et al. [1xAltered transcription in yeast expressing expanded polyglutamine. Hughes, R.E. et al. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 13201–13206Crossref | PubMed | Scopus (99)See all References][1] performed DNA microarray analyses in yeast strains expressing nuclear-targeted, polyQ tracts. Transcriptional alterations were identified, including, most prominently, repression of a small set of genes, several of which are specific for phosphate metabolism. These changes are remarkably similar to the altered gene expression profiles associated with deletion of components of the SAGA histone acetyltransferase complex. Consistent with an effect of polyQ on histone acetylation, the promoter from one affected gene (PHO84) was repressed by polyQ, and this effect was offset by trichostatin A, a histone deacetylase inhibitor. These results not only support transcriptional dysregulation as a pathogenic mechanism of polyQ diseases, but substantiate the growing body of evidence that polyQ targets the phylogenetically conserved histone acetylation machinery.An important concern regarding polyQ-mediated transcriptional dysregulation as a cause of neuronal dysfunction is the issue of disease specificity. Although the CAG repeat expansion diseases are related, each exhibits distinct clinical and pathological differences. How does transcriptional dysregulation by expanded polyQ tracts account for these differences? Despite this caveat, the discovery that polyQ-mediated transcriptional defects seen in animal models might occur in yeast, and be mediated through conserved components of the transcriptional machinery, offers a powerful experimental system to address the mechanisms underlying polyQ-mediated neuronal dysfunction.