title: Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), however, the means by which neurodegeneration occurs remains obscure. There is evidence that mutant Htt interacts with transcription factors leading to reduced histone acetylation. We report that administration of the histone deacetylase inhibitor phenylbutyrate after onset of symptoms in a transgenic mouse model of HD significantly extends survival and attenuates both gross brain and neuronal atrophy. Administration of phenylbutyrate increased brain histone acetylation and decreased histone methylation levels as assessed by both immunocytochemistry and Western blots. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, New York 10021, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gardian
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
authors.forename: Dong-Kug
authors.initials: DK
authors.lastname: Choi
authors.forename: Peter
authors.initials: P
authors.lastname: Klivenyi
authors.forename: Jason
authors.initials: J
authors.lastname: Gregorio
authors.forename: James K
authors.initials: JK
authors.lastname: Kubilus
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Brett
authors.initials: B
authors.lastname: Langley
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000107:Acetylation; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010654:Phenylbutyrates; D025801:Ubiquitin