D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.

Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neur...

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Autores principales:	Soyeon Lim, Adrianne S Chesser, Jonathan C Grima, Phillip M Rappold, David Blum, Serge Przedborski, Kim Tieu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8488f6096848471e9ca9f2beab9c1e23
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spelling	oai:doaj.org-article:8488f6096848471e9ca9f2beab9c1e232021-11-04T06:08:49ZD-β-hydroxybutyrate is protective in mouse models of Huntington's disease.1932-620310.1371/journal.pone.0024620https://doaj.org/article/8488f6096848471e9ca9f2beab9c1e232011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21931779/?tool=EBIhttps://doaj.org/toc/1932-6203Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neuroprotective properties of the mitochondrial energizing ketone body, D-β-hydroxybutyrate (DβHB), in the 3-nitropropionic acid (3-NP) toxic and the R6/2 genetic model of HD. In mice treated with 3-NP, a complex II inhibitor, infusion of DβHB attenuates motor deficits, striatal lesions, and microgliosis in this model of toxin induced-striatal neurodegeneration. In transgenic R6/2 mice, infusion of DβHB extends life span, attenuates motor deficits, and prevents striatal histone deacetylation. In PC12 cells with inducible expression of mutant huntingtin protein, we further demonstrate that DβHB prevents histone deacetylation via a mechanism independent of its mitochondrial effects and independent of histone deacetylase inhibition. These pre-clinical findings suggest that by simultaneously targeting the mitochondrial and the epigenetic abnormalities associated with mutant huntingtin, DβHB may be a valuable therapeutic agent for HD.Soyeon LimAdrianne S ChesserJonathan C GrimaPhillip M RappoldDavid BlumSerge PrzedborskiKim TieuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e24620 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Soyeon Lim Adrianne S Chesser Jonathan C Grima Phillip M Rappold David Blum Serge Przedborski Kim Tieu D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
description	Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neuroprotective properties of the mitochondrial energizing ketone body, D-β-hydroxybutyrate (DβHB), in the 3-nitropropionic acid (3-NP) toxic and the R6/2 genetic model of HD. In mice treated with 3-NP, a complex II inhibitor, infusion of DβHB attenuates motor deficits, striatal lesions, and microgliosis in this model of toxin induced-striatal neurodegeneration. In transgenic R6/2 mice, infusion of DβHB extends life span, attenuates motor deficits, and prevents striatal histone deacetylation. In PC12 cells with inducible expression of mutant huntingtin protein, we further demonstrate that DβHB prevents histone deacetylation via a mechanism independent of its mitochondrial effects and independent of histone deacetylase inhibition. These pre-clinical findings suggest that by simultaneously targeting the mitochondrial and the epigenetic abnormalities associated with mutant huntingtin, DβHB may be a valuable therapeutic agent for HD.
format	article
author	Soyeon Lim Adrianne S Chesser Jonathan C Grima Phillip M Rappold David Blum Serge Przedborski Kim Tieu
author_facet	Soyeon Lim Adrianne S Chesser Jonathan C Grima Phillip M Rappold David Blum Serge Przedborski Kim Tieu
author_sort	Soyeon Lim
title	D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
title_short	D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
title_full	D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
title_fullStr	D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
title_full_unstemmed	D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
title_sort	d-β-hydroxybutyrate is protective in mouse models of huntington's disease.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/8488f6096848471e9ca9f2beab9c1e23
work_keys_str_mv	AT soyeonlim dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease AT adrianneschesser dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease AT jonathancgrima dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease AT phillipmrappold dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease AT davidblum dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease AT sergeprzedborski dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease AT kimtieu dbhydroxybutyrateisprotectiveinmousemodelsofhuntingtonsdisease
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D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.

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