Modulation of polyglutamine-induced cell death by genes identified by expression profiling
Kita, H., Carmichael, J., Swartz, J., Muro, S., Wyttenbach, A., Matsubara, K., Rubinsztein, D.C. and Kato, K. (2002) Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Human Molecular Genetics, 11, (19), 2279-2287.
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The majority of triplet-repeat diseases are caused by mutated genes with an extended polyglutamine tract, exemplified by Huntington's disease (HD). In order to model HD pathogenesis in a controlled system, we developed stable PC12 cell lines that express exon 1 fragments of the huntingtin gene with 23 or 74 polyglutamines driven by an inducible doxycycline (dox)-sensitive promoter (HD-23Q or HD-74Q). We aimed to identify early perturbations induced by the mutation by studying expression levels of 1824 genes at 0, 5, 10 and 18 hours after induction, using adaptor-tagged competitive PCR (ATAC–PCR). At these time points, the cells show no appreciable death or mitochondrial impairment and very low inclusion levels. A total of 126 genes, including 69 known genes, exhibited statistically significant alterations in the HD-74Q cell lines but no changes in the HD-23Q lines. We tested 11 of these genes for their abilities to modulate polyglutamine-induced cell death in transiently transfected cell models. Five genes [glucose transporter 1 (Glut1), phosphofructokinase muscle isozyme (Pfkm), prostate glutathione-S -transferase 2 (Gstm2), RNA-binding motif protein 3 (Rbm3) and KRAB-A interacting protein 1 (Krip-1)] significantly suppressed cell death in both neuronal precursor and non-neuronal cell lines, suggesting that these transcriptional changes were relevant to polyglutamine pathology. The efficient recovery of functionally relevant genes supports the utility of gene expression profiling for discovering pathways related to pathogenesis, and the importance of analyzing molecular events in the early stages of disease.
|Subjects:||Q Science > QH Natural history > QH426 Genetics
Q Science > QH Natural history > QH301 Biology
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||08 Aug 2008|
|Last Modified:||01 Jun 2011 17:03|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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