Basic Research for Development of Novel Therapeutics of Polyglutamine Diseases through Transcriptional Regulation

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In this study, we investigated changes of gene expression profiles by transcriptome and proteome analyses. We have found multiple candidate genes whose expression changes in specific types of neurons affected in polyQ diseases. Among them, we currently focus on hsp70 whose expression was dramatically up-regulated instriatal neurons by mutant huntingtin expression but not by mutant ataxin-1. The remarkable increase was not observed in other types of neurons such as granule cells or cortical neurons. We further analyzed molecular mechanisms underlying transcriptional upregulation, and found that HSF1, a famous transcription factor affecting expression of heat shock proteins, is not involve in the upregulation by mutant htt. Instead, we found another transcription factor p53 is critically involved in the regulation of hsp70 expression.We plan to use the result for developing nove therapeutics in the future.