Huntington's Disease Antisense Transcript

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DESCRIPTION (provided by applicant): Huntington's disease (HD) is a fatal neurodegenerative disorder, affecting about 30,000 people in the United State, and caused by an expansion of a CAG repeat (encoding polyglutamine) in the gene huntingtin located on chromosome 4p. While ample evidence supports a major role for polyglutamine toxicity in the pathogenesis of Huntington's disease (HD), the complete explanation for HD pathogenesis remains elusive. Recent evidence suggests that transcripts antisense to genes are present throughout the genome. In particular, antisense transcripts with potential roles in disease pathogenesis have been detected at the locus of a number of repeat expansion diseases, including fragile X, myotonic dystrophy type 1, spinocerebellar ataxia type 8, and Huntington's disease-like 2. Our preliminary data indicates that 1) an antisense transcript spanning the CAG/CTG repeat region at the HD locus (termed huntingtin antisense, abbreviated HTTAS) exists and is expressed in multiple brain regions; 2) HTTAS promoter activity is inversely proportional to the length of the CAG/CTG repeat, 3) HTTAS is decreased in HD brain compared to control brain, and 4) exogenous overexpression of HTTAS decreases huntingtin (HTT) levels, while knockdown of HTTAS increases HTT levels. We have also developed a series of constructs modeling the HD locus, which demonstrates the repeat-length dependent influence of HTTAS on HTT. Based on this initial data, we hypothesize that HTTAS influences HTT expression in a repeat length-dependent manner, with consequent impact on HD pathogenesis. We will test this hypothesis in Aim 1 by mapping the complete HTTAS gene in the human and mouse genome, confirming the repeat-length dependent actiivty of the promoter, and determining the pattern of HTTAS1 expression in normal and HD brain. In Aim 2, we will use cell models to determine the effect of HTTAS on HTT expression both in cis and in trans, and in the setting of normal and expanded repeats. These experiments will enable us to establish the existence and function of HTTAS, and provide us with sufficient preliminary data to compete for long term funding for this project. Ultimately, understanding the relationship between HTT and HTTAS will provide new insights into the mechanism of HD pathogenesis and may lead to the development of novel therapeutic strategies. PUBLIC HEALTH RELEVANCE: Antisense transcripts appear to regulate mutant transcripts in a number of diseases, including several repeat expansion diseases. We propose to test the hypothesis that an antisense transcript at the HD locus regulates huntingtin. If confirmed, antisense regulation would provide a new approach to understanding the pathogenesis of HD, and new approaches for developing therapeutic agents for HD.