Microarrays and polyglutamine disorders: reports from the Hereditary Disease Array Group.

Abstract

Advances in molecular biology and genetics have allowed researchers to probe function and dysfunction at the level of the individual gene and/or protein. The integration of such information into an understanding of function has been a challenge facing all molecular geneticists and has contributed to the widening gap between molecular and systems scientists. In the neurosciences, this rift is especially dramatic. The ability to simultaneously monitor changes in the expression of thousands of genes using DNA microarrays has the potential to provide a global or ‘genomic’ view of brain function/ dysfunction. Two important barriers in the application of this technology to the study of neurological disease have been the availability of high-powered analytical approaches and appropriate genetic models. This issue of Human Molecular Genetics contains six contributions that approach these hurdles. These papers are centered on the application of DNA microarrays to survey alterations in gene expression associated with the expression of mutant polyglutamine proteins. A consortium headed by Dr Jim Olson of the Fred Hutchinson Cancer Research Center in Seattle and funded by the Hereditary Disease Foundation initiated this effort. Thus, this work is focused on the effects of expressing a mutant form of the Huntington disease (HD) gene product, huntingtin. Three papers, two by Luthi-Carter and colleagues (1,2) and one from Chan and co-workers (3), examine polyglutamineinduced changes in gene expression using several mouse models of HD. In the Luthi-Carter et al. contributions, mice expressing a truncated form of mutant huntingtin are examined. The first paper provides data that, in R6/2 mice (the often designated Bates mouse), a considerable number of genes have an altered pattern of expression and this pattern shows little sign of regional specificity (1). These are consistent with the previous pathological data indicating that this mouse model of HD shows little sign of the regional-specificity of disease as seen in patients. The second paper from the Luthi-Carter group compares gene expression changes between mouse models of dentatorubral–pallidoluysian atrophy and HD (2). At least in the cerebella of these mice, there was a considerable overlap in the genes showing altered gene expression. Thus, polyglutamine-induced changes in gene expression can be identified that are independent of the protein context in which the glutamine tract is located. Perhaps such context-independent genes reflect pathways that are common among the different polyglutamine