title: Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets.
abstract: Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mali
authors.initials: M
authors.lastname: Jiang
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.forename: Jinrong
authors.initials: J
authors.lastname: Fu
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Jeong
authors.forename: Tim
authors.initials: T
authors.lastname: West
authors.forename: Lan
authors.initials: L
authors.lastname: Xiang
authors.forename: Qi
authors.initials: Q
authors.lastname: Peng
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Hou
authors.forename: Huan
authors.initials: H
authors.lastname: Cai
authors.forename: Tamara
authors.initials: T
authors.lastname: Seredenina
authors.forename: Nicolas
authors.initials: N
authors.lastname: Arbez
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhu
authors.forename: Katherine
authors.initials: K
authors.lastname: Sommers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Qian
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Zhang
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.forename: Kellie L K
authors.initials: KL
authors.lastname: Tamashiro
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497929:Ppp1r1b protein, mouse; D020813:Receptor, trkB; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1