Abstract

Huntington's disease (HD), MIM 143100, is a dominantly inherited progressive neurodegenerative disorder characterised by motor, behavioural and cognitive dysfunction, caused by an expanded CAG repeat region in exon 1 of the HTT gene. This mutation results in the presence of an abnormally long polyglutamine tract in the encoded protein, huntingtin. Research into this disorder has conventionally focused on neurological symptoms and brain pathology, particularly neurodegeneration in the basal ganglia and cerebral cortex. Mutant huntingtin is, however, ubiquitously expressed throughout the body. Contrary to earlier thinking, HD is also associated with abnormalities in peripheral tissues. Due to obvious problems in obtaining brain tissue, these peripheral tissues can be studied to elucidate pathogenetic mechanism (still not well understood) of the disease as well as identifying disease biomarkers. Peripheral tissue dermal fibroblasts, which have the same ectodermal origin as CNS cells, may represent an alternative source for biological studies. Furthermore, contrary to peripheral blood cells, this cell type is not directly exposed to drugs. We performed gene expression profile analysis of human fibroblasts obtained from HD patients and healthy controls matched by age and sex. The study was performed using the whole genome Affymetrix HG U133 plus 2.0 arrays. Preliminary data obtained indicate that 451 genes are upregulated twofold or greater in patients compared with controls while 17 are downregulated. This study allowed us to evidence the modulation at the transcriptional level of a discrete number of genes relevant in biological processes which are altered in the disease—processes such as transcription and its regulation, apoptosis, regulation of actin cytoskeleton, inositol phosphate metabolism and vesicle mediated transport. We plan to extend this type of analysis to a larger number of cases and controls and to confirm the differential expression of interesting genes both at the RNA and protein levels. The data generated by this study could provide novel clues on the Huntington pathogenesis and lead to the identification of a set of mRNAs that appear to be useful as biomarkers of the disease.