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

Soyeon Lim,Jonathan C Grima,Kim Tieu,Serge Przedborski,Phillip M Rappold,Adrianne S Chesser,David Blum,Toshi Shioda

doi:10.1371/journal.pone.0024620

Abstract

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.

Highlights

Huntington’s disease (HD) is a genetic neurological disorder caused by the expansion of a trinucleotide CAG repeat that encodes the polyglutamine region in the huntingtin protein
Metabolic impairment precedes the demise of striatal neurons [5,6] and a reduction in mitochondrial respiration [7] have been detected in HD patients– consistent with the loss of complex II function induced by mutant huntingtin [8,9,10]
DbHB attenuates striatal lesions induced by 3-nitropropionic acid (3-NP) We previously demonstrated that DbHB conferred neuroprotection through the generation of succinate, a complex II substrate, in order to bypass complex I inhibition in the MPTP mouse model of PD [28]

Summary

Introduction

Huntington’s disease (HD) is a genetic neurological disorder caused by the expansion of a trinucleotide CAG repeat that encodes the polyglutamine region in the huntingtin protein. Metabolic impairment precedes the demise of striatal neurons [5,6] and a reduction in mitochondrial respiration [7] have been detected in HD patients– consistent with the loss of complex II function induced by mutant huntingtin (mhtt) [8,9,10]. It is conceivable that mhtt can perturb neuronal function and survival by interfering with the activities of transcription factors. Consistent with this theory, treatment with various histone deacetylase (HDAC) inhibitors improves motor dysfunction, brain pathologies and life expectancy in animal models of HD [19,20,21,22,23]

Methods

Results

Conclusion