Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice.
The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.
Ferrante
Robert J
RJ
Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, USA. rjferr@bu.edu
Kubilus
James K
JK
Lee
Junghee
J
Ryu
Hoon
H
Beesen
Ayshe
A
Zucker
Birgit
B
Smith
Karen
K
Kowall
Neil W
NW
Ratan
Rajiv R
RR
Luthi-Carter
Ruth
R
Hersch
Steven M
SM
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002087:Butyrates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009574:Nitro Compounds; D010641:Phenotype; D011422:Propionates; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009574:Nitro Compounds; D011422:Propionates; D016329:Sp1 Transcription Factor; C015392:3-nitropropionic acid