AUTHOR=Reisbitzer Annika , Hollitzer Cecilia , Geraci Adriana , Schaefer Jessye , Burghaus Maximilian , Bruns Jonas , Urban Joachim , Kurz Thomas , Krauß Sybille 

TITLE=Inhibition of class IIa HDACs reduces mutant HTT aggregation by affecting RNA stability

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 18 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2025.1579194

DOI=10.3389/fnmol.2025.1579194

ISSN=1662-5099

ABSTRACT=IntroductionHuntington’s disease (HD) is a fatal inherited neurological disorder for which there are no curative treatments available. Patients suffer from progressive impairment in cognitive and motor functions. Transcriptional dysregulation is a major molecular disease mechanism of HD. Transcription is regulated by a variety of epigenetic marks, including acetylation of histone proteins. This acetylation is controlled by opposing activities of histone acetyltransferases and histone deacetylases (HDACs). Based on recent observations that inhibition of HDACs can ameliorate disease phenotypes in different model systems ranging from cell culture to yeast, Drosophila and mouse models, the development of HDAC inhibitors as therapeutics for HD is promising. Recently, class IIa HDAC enzymes (4, 5, 7, 9) and specifically HDAC 4, have been identified as potential targets for the treatment of HD.MethodsHere, we tested a set of novel class IIa HDAC inhibitors for their efficiency in two different HD models: an HD cell line model and a Drosophila model.ResultsThe selective class IIa HDAC inhibitor 1a led to a significant reduction of HTT aggregation and ameliorated the disease phenotype in vivo. The reduction in HTT aggregates was caused by reduced RNA levels in treated samples, due to decreased RNA stability.DiscussionOur data suggest a so far unknown mode of action of HDAC class IIa inhibitors by affecting HTT transcript levels.