D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease

Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 09/2011; 6(9):e24620. DOI: 10.1371/journal.pone.0024620
Source: PubMed


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.

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    • "The beneficial pleiotropic effects of ketone bodies have been reported other than the role of metabolic fuel. D-beta-hydroxybutyrate (D-BHB), a major circulating ketone body, has been demonstrated to be effective in neurological disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease in animal models and humans [12-14]. In addition, D-BHB has been found to attenuate corneal disorder [15,16], retinal degeneration [17], and bone loss from ovariectomy [18]. "
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    ABSTRACT: Mouse models of human diseases are created both to understand the pathogenesis of the disorders and to find successful therapies for them. This work is the second part in a series of reviews of mouse models of polyglutamine (polyQ) hereditary disorders and focuses on in vivo experimental therapeutic approaches. Like part I of the polyQ mouse model review, this work is supplemented with a table that contains data from experimental studies of therapeutic approaches in polyQ mouse models. The aim of this review was to characterize the benefits and outcomes of various therapeutic strategies in mouse models. We examine whether the therapeutic strategies are specific to a single disease or are applicable to more than one polyQ disorder in mouse models. In addition, we discuss the suitability of mouse models in therapeutic approaches. Although the majority of therapeutic studies were performed in mouse models of Huntington disease, similar strategies were also used in other disease models. Electronic supplementary material The online version of this article (doi:10.1007/s12035-012-8316-3) contains supplementary material, which is available to authorized users.
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