BRIEF RESEARCH REPORT article

Front. Mol. Neurosci.

Sec. Molecular Signalling and Pathways

Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1579194

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

Provisionally accepted
  • 1University of Siegen, Siegen, Germany
  • 2Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
  • 3Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, 40225 Düsseldorf, Germany

The final, formatted version of the article will be published soon.

Introduction: Huntington'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.Methods: Here, 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.The 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. Discussion: Our data suggest a so far unknown mode of action of HDAC class IIa inhibitors by affecting HTT transcript levels.

Keywords: Huntington's disease, Class IIa histone deacetylases, RNA Stability, RNA-Binding Protein, polyglutamine protein

Received: 18 Feb 2025; Accepted: 04 Jun 2025.

Copyright: © 2025 Reisbitzer, Hollitzer, Geraci, Bruns, Urban, Kurz and Krauß. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Thomas Kurz, Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, 40225 Düsseldorf, Germany
Sybille Krauß, University of Siegen, Siegen, Germany

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