{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:27:38Z","timestamp":1792114058308,"version":"4.4.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Huntington\u2019s 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, <jats:italic>Drosophila<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 <jats:italic>Drosophila<\/jats:italic> model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The selective class IIa HDAC inhibitor 1a led to a significant reduction of HTT aggregation and ameliorated the disease phenotype <jats:italic>in vivo<\/jats:italic>. The reduction in HTT aggregates was caused by reduced RNA levels in treated samples, due to decreased RNA stability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data suggest a so far unknown mode of action of HDAC class IIa inhibitors by affecting <jats:italic>HTT<\/jats:italic> transcript levels.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2025.1579194","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:45:46Z","timestamp":1750225546000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of class IIa HDACs reduces mutant HTT aggregation by affecting RNA stability"],"prefix":"10.3389","volume":"18","author":[{"given":"Annika","family":"Reisbitzer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Hollitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Geraci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessye","family":"Schaefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Burghaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Bruns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Urban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kurz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sybille","family":"Krau\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"115907","DOI":"10.1016\/j.ejmech.2023.115907","article-title":"5-(Trifluoromethyl)-1,2,4-oxadiazole (TFMO)-based highly selective class IIa HDAC inhibitors exhibit synergistic anticancer activity in combination with bortezomib","volume":"263","author":"Asfaha","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3398","DOI":"10.3390\/ijms232113398","article-title":"The novel class IIa selective histone deacetylase inhibitor YAK540 is synergistic with Bortezomib in leukemia cell lines","volume":"23","author":"Bollmann","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"84338","DOI":"10.7554\/eLife.84338","article-title":"FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS\/FTD","volume":"12","author":"Fujino","year":"2023","journal-title":"eLife"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/s41467-017-00911-y","article-title":"HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients","volume":"8","author":"Guo","year":"2017","journal-title":"Nat. Commun."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1073\/pnas.0437870100","article-title":"Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease","volume":"100","author":"Hockly","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1093\/hmg\/ddl013","article-title":"Regional and cellular gene expression changes in human Huntington's disease brain","volume":"15","author":"Hodges","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"5280","DOI":"10.1093\/hmg\/dds379","article-title":"Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin-proteasomal and autophagy systems","volume":"21","author":"Jia","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"3021","DOI":"10.3390\/ijms241613021","article-title":"From pathogenesis to therapeutics: a review of 150 years of Huntington's disease research","volume":"24","author":"Jiang","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"35236","DOI":"10.1038\/srep35236","article-title":"FUS\/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice","volume":"6","author":"Kino","year":"2016","journal-title":"Sci. Rep."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"55911","DOI":"10.7554\/eLife.55911","article-title":"Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice","volume":"9","author":"Kovalenko","year":"2020","journal-title":"eLife"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1093\/hmg\/ddm133","article-title":"Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage","volume":"16","author":"Kuhn","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"12445","DOI":"10.1021\/acs.jmedchem.2c01149","article-title":"Developing HDAC4-selective protein degraders to investigate the role of HDAC4 in Huntington's disease pathology","volume":"65","author":"Macabuag","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"751033","DOI":"10.3389\/fgene.2021.751033","article-title":"A systematic review of transcriptional dysregulation in Huntington's disease studied by RNA sequencing","volume":"12","author":"Malla","year":"2021","journal-title":"Front. Genet."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e41423","DOI":"10.1371\/journal.pone.0041423","article-title":"Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease","volume":"7","author":"McFarland","year":"2012","journal-title":"PLoS One"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e27746","DOI":"10.1371\/journal.pone.0027746","article-title":"SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6\/2 mouse model of Huntington's disease","volume":"6","author":"Mielcarek","year":"2011","journal-title":"PLoS One"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"e1001717","DOI":"10.1371\/journal.pbio.1001717","article-title":"HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration","volume":"11","author":"Mielcarek","year":"2013","journal-title":"PLoS Biol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1111\/febs.13061","article-title":"Class IIa HDACs \u2013 new insights into their functions in physiology and pathology","volume":"282","author":"Parra","year":"2014","journal-title":"FEBS J."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S0092-8674(00)80514-0","article-title":"Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo","volume":"90","author":"Scherzinger","year":"1997","journal-title":"Cell"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1016\/j.jmb.2019.01.034","article-title":"Deregulated splicing is a major mechanism of RNA-induced toxicity in Huntington's disease","volume":"431","author":"Schilling","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.nbd.2011.07.001","article-title":"What have we learned from gene expression profiles in Huntington's disease?","volume":"45","author":"Seredenina","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.phrs.2015.08.002","article-title":"Transcriptional dysregulation in Huntington's disease: the role of histone deacetylases","volume":"100","author":"Sharma","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/35099568","article-title":"Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila","volume":"413","author":"Steffan","year":"2001","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1021\/acsmedchemlett.0c00532","article-title":"Evaluation of 5-(Trifluoromethyl)-1,2,4-oxadiazole-based class IIa HDAC inhibitors for Huntington's disease","volume":"12","author":"Stott","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1111\/bcp.12512","article-title":"An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease","volume":"79","author":"Sussmuth","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"686995","DOI":"10.3389\/fnmol.2021.686995","article-title":"Potential therapeutic role of HDAC inhibitors in FUS-ALS","volume":"14","author":"Tejido","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"E3027","DOI":"10.1073\/pnas.1311323110","article-title":"Targeting H3K4 trimethylation in Huntington disease","volume":"110","author":"Vashishtha","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1091\/mbc.12.5.1393","article-title":"Accumulation of mutant Huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation","volume":"12","author":"Waelter","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"24840","DOI":"10.1073\/pnas.1908113116","article-title":"Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington's disease","volume":"116","author":"Yildirim","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2025.1579194\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:45:46Z","timestamp":1750225546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2025.1579194\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":28,"alternative-id":["10.3389\/fnmol.2025.1579194"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2025.1579194","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"article-number":"1579194"}}