title: Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease.
abstract: An expanded CAG repeat is the underlying genetic defect in Huntington disease, a disorder characterized by motor, psychiatric and cognitive deficits and striatal atrophy associated with neuronal loss. An accurate animal model of this disease is crucial for elucidation of the underlying natural history of the illness and also for testing experimental therapeutics. We established a new yeast artificial chromosome (YAC) mouse model of HD with the entire human HD gene containing 128 CAG repeats (YAC128) which develops motor abnormalities and age-dependent brain atrophy including cortical and striatal atrophy associated with striatal neuronal loss. YAC128 mice exhibit initial hyperactivity, followed by the onset of a motor deficit and finally hypokinesis. The motor deficit in the YAC128 mice is highly correlated with striatal neuronal loss, providing a structural correlate for the behavioral changes. The natural history of HD-related changes in the YAC128 mice has been defined, demonstrating the presence of huntingtin inclusions after the onset of behavior and neuropathological changes. The HD-related phenotypes of the YAC128 mice show phenotypic uniformity with low inter-animal variability present, which together with the age-dependent striatal neurodegeneration make it an ideal mouse model for the assessment of neuroprotective and other therapeutic interventions.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Slow
authors.forename: Jeremy
authors.initials: J
authors.lastname: van Raamsdonk
authors.forename: Daniel
authors.initials: D
authors.lastname: Rogers
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Coleman
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Rosemary
authors.initials: R
authors.lastname: Oh
authors.forename: Nagat
authors.initials: N
authors.lastname: Bissada
authors.forename: Sazzad M
authors.initials: SM
authors.lastname: Hossain
authors.forename: Yu-Zhou
authors.initials: YZ
authors.lastname: Yang
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Simpson
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000367:Age Factors; D000818:Animals; D015139:Blotting, Southern; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D018244:Chromosomes, Artificial, Yeast; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008854:Microscopy, Electron; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D013997:Time Factors; D018911:Trinucleotide Repeats
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012313:RNA