title: D-β-hydroxybutyrate is protective in mouse models of Huntington's disease.
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.
authors.affiliation: Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Adrianne S
authors.initials: AS
authors.lastname: Chesser
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Grima
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Rappold
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000627:therapeutic use*; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D006657:Histones / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds / Q000627:therapeutic use; D016716:PC12 Cells; D011422:Propionates / Q000627:therapeutic use; D051381:Rats
chemical_list: D006657:Histones; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid; D020155:3-Hydroxybutyric Acid