trichostatin-a and Machado-Joseph-Disease

Although expansion of trinucleotide repeats accounts for over 30 human diseases, mechanisms of repeat instability remain poorly understood. We show that a Drosophila model for the CAG/polyglutamine (polyQ) disease spinocerebellar ataxia type 3 recapitulates key features of human CAG-repeat instability, including large repeat changes and strong expansion bias. Instability is dramatically enhanced by transcription and modulated by nuclear excision repair and a regulator of DNA repair adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB)-binding protein-a histone acetyltransferase (HAT) whose decreased activity contributes to polyQ disease. Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability.

Topics: Alleles; Animals; Animals, Genetically Modified; Anticipation, Genetic; CREB-Binding Protein; DNA Repair; Drosophila melanogaster; Drosophila Proteins; Female; Fragile X Syndrome; Genomic Instability; Histone Deacetylase Inhibitors; Humans; Huntington Disease; Hydroxamic Acids; Machado-Joseph Disease; Male; Models, Animal; Peptides; Transcription, Genetic; Transgenes; Trinucleotide Repeat Expansion; Trinucleotide Repeats