title: Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease.
abstract: Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.
authors.affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors.forename: Motomasa
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Machida
authors.forename: Sanyong
authors.initials: S
authors.lastname: Niu
authors.forename: Tetsurou
authors.initials: T
authors.lastname: Ikeda
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Jana
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Nekooki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009211:Myoglobin / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D014199:Trehalose / Q000627:therapeutic use*
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009211:Myoglobin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D014199:Trehalose; D005947:Glucose