title: Towards a transgenic model of Huntington's disease in a non-human primate.
abstract: Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA.
authors.forename: Shang-Hsun
authors.initials: SH
authors.lastname: Yang
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Cheng
authors.forename: Heather
authors.initials: H
authors.lastname: Banta
authors.forename: Karolina
authors.initials: K
authors.lastname: Piotrowska-Nitsche
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Yang
authors.forename: Eric C H
authors.initials: EC
authors.lastname: Cheng
authors.forename: Brooke
authors.initials: B
authors.lastname: Snyder
authors.forename: Katherine
authors.initials: K
authors.lastname: Larkin
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Jack
authors.initials: J
authors.lastname: Orkin
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Fang
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Bachevalier
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Zola
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Li
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: Anthony W S
authors.initials: AW
authors.lastname: Chan
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002819:Chorea / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008253:Macaca mulatta / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D016019:Survival Analysis; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine