Histone deacetylase (HDAC) inhibitors reduce polyglutamine-dependent neurodegeneration in Drosophila. The study shows that the polyglutamine-containing domain of the huntingtin (Htt) protein interacts with acetyltransferase domains of CBP and P/CAF, inhibiting their activity and reducing acetylation of histones H3 and H4. This reduction in acetylation is reversed by HDAC inhibitors, which also arrest neuronal degeneration and reduce lethality in Drosophila models of polyglutamine diseases. These findings suggest that HDAC inhibitors may slow or prevent neurodegeneration in Huntington's disease and other polyglutamine-repeat disorders, even after symptoms appear. The study also shows that expanded polyglutamine repeats cause pathology by inhibiting acetyltransferase activity, and that HDAC inhibitors can reverse this effect. The results indicate that acetylation levels are critical in polyglutamine pathogenesis, and that HDAC inhibitors may be a promising therapeutic approach for Huntington's disease and related conditions. The study was conducted using in vitro and in vivo experiments, including cell culture and Drosophila models, and involved the use of various molecular techniques such as GST pull-down assays and western blotting. The research was supported by several funding sources, including the Hereditary Disease Foundation's Cure HD Initiative and the National Institutes of Health.Histone deacetylase (HDAC) inhibitors reduce polyglutamine-dependent neurodegeneration in Drosophila. The study shows that the polyglutamine-containing domain of the huntingtin (Htt) protein interacts with acetyltransferase domains of CBP and P/CAF, inhibiting their activity and reducing acetylation of histones H3 and H4. This reduction in acetylation is reversed by HDAC inhibitors, which also arrest neuronal degeneration and reduce lethality in Drosophila models of polyglutamine diseases. These findings suggest that HDAC inhibitors may slow or prevent neurodegeneration in Huntington's disease and other polyglutamine-repeat disorders, even after symptoms appear. The study also shows that expanded polyglutamine repeats cause pathology by inhibiting acetyltransferase activity, and that HDAC inhibitors can reverse this effect. The results indicate that acetylation levels are critical in polyglutamine pathogenesis, and that HDAC inhibitors may be a promising therapeutic approach for Huntington's disease and related conditions. The study was conducted using in vitro and in vivo experiments, including cell culture and Drosophila models, and involved the use of various molecular techniques such as GST pull-down assays and western blotting. The research was supported by several funding sources, including the Hereditary Disease Foundation's Cure HD Initiative and the National Institutes of Health.