Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears ear...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Lara Moumné, Ken Campbell, David Howland, Yingbin Ouyang, Gillian P Bates
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df609b2a2ad04b188d9cdff1e7b1b680
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:df609b2a2ad04b188d9cdff1e7b1b680
record_format	dspace
spelling	oai:doaj.org-article:df609b2a2ad04b188d9cdff1e7b1b6802021-11-18T07:28:40ZGenetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.1932-620310.1371/journal.pone.0031080https://doaj.org/article/df609b2a2ad04b188d9cdff1e7b1b6802012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22347433/?tool=EBIhttps://doaj.org/toc/1932-6203Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression and has been recapitulated across multiple HD models. Altered histone acetylation has been proposed to underlie this transcriptional dysregulation and histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), have been shown to improve polyglutamine-dependent phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as SAHA display toxic side-effects. To better understand the mechanism underlying this potential therapeutic benefit and to dissociate the beneficial and toxic effects of SAHA, we set out to identify the specific HDAC(s) involved in this process. For this purpose, we are exploring the effect of the genetic reduction of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The study presented here focuses on HDAC3, which, as a class I HDAC, is one of the preferred targets of SAHA and is directly involved in histone deacetylation. To evaluate a potential benefit of Hdac3 genetic reduction in R6/2, we generated a mouse carrying a critical deletion in the Hdac3 gene. We confirmed that the complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 inhibition, we used Hdac3(+/-) heterozygotes to reduce nuclear HDAC3 levels in R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiological or behavioural phenotypes and has no effect on molecular changes including dysregulated transcripts. We conclude that HDAC3 should not be considered as the major mediator of the beneficial effect induced by SAHA and other HDAC inhibitors in HD.Lara MoumnéKen CampbellDavid HowlandYingbin OuyangGillian P BatesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31080 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lara Moumné Ken Campbell David Howland Yingbin Ouyang Gillian P Bates Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.
description	Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression and has been recapitulated across multiple HD models. Altered histone acetylation has been proposed to underlie this transcriptional dysregulation and histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), have been shown to improve polyglutamine-dependent phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as SAHA display toxic side-effects. To better understand the mechanism underlying this potential therapeutic benefit and to dissociate the beneficial and toxic effects of SAHA, we set out to identify the specific HDAC(s) involved in this process. For this purpose, we are exploring the effect of the genetic reduction of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The study presented here focuses on HDAC3, which, as a class I HDAC, is one of the preferred targets of SAHA and is directly involved in histone deacetylation. To evaluate a potential benefit of Hdac3 genetic reduction in R6/2, we generated a mouse carrying a critical deletion in the Hdac3 gene. We confirmed that the complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 inhibition, we used Hdac3(+/-) heterozygotes to reduce nuclear HDAC3 levels in R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiological or behavioural phenotypes and has no effect on molecular changes including dysregulated transcripts. We conclude that HDAC3 should not be considered as the major mediator of the beneficial effect induced by SAHA and other HDAC inhibitors in HD.
format	article
author	Lara Moumné Ken Campbell David Howland Yingbin Ouyang Gillian P Bates
author_facet	Lara Moumné Ken Campbell David Howland Yingbin Ouyang Gillian P Bates
author_sort	Lara Moumné
title	Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.
title_short	Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.
title_full	Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.
title_fullStr	Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.
title_full_unstemmed	Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.
title_sort	genetic knock-down of hdac3 does not modify disease-related phenotypes in a mouse model of huntington's disease.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/df609b2a2ad04b188d9cdff1e7b1b680
work_keys_str_mv	AT laramoumne geneticknockdownofhdac3doesnotmodifydiseaserelatedphenotypesinamousemodelofhuntingtonsdisease AT kencampbell geneticknockdownofhdac3doesnotmodifydiseaserelatedphenotypesinamousemodelofhuntingtonsdisease AT davidhowland geneticknockdownofhdac3doesnotmodifydiseaserelatedphenotypesinamousemodelofhuntingtonsdisease AT yingbinouyang geneticknockdownofhdac3doesnotmodifydiseaserelatedphenotypesinamousemodelofhuntingtonsdisease AT gillianpbates geneticknockdownofhdac3doesnotmodifydiseaserelatedphenotypesinamousemodelofhuntingtonsdisease
_version_	1718423443035127808

Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington's disease.

Ejemplares similares