title: Pathogenic cellular phenotypes are germline transmissible in a transgenic primate model of Huntington's disease.
abstract: A transgenic primate model for Huntington's Disease (HD) first reported by our group that (HD monkeys) carry the mutant Huntingtin (HTT) gene with expanded polyglutamine (CAG) repeats and, develop chorea, dystonia, and other involuntary motor deficiencies similar to HD [ 1 ]. More recently, we have found that longitudinal magnetic resonance imaging of the HD monkey brain revealed significant atrophy in regions associated with cognitive deficits symptomatic in HD patients, providing the first animal model which replicates clinical phenotypes of diagnosed humans. Here we report germline transmission of the pathogenic mutant HTT in HD monkey by the production of embryos and subsequent derivation of HD monkey embryonic stem cells (rHD-ESCs) using HD monkey sperm. rHD-ESCs inherit mutant HTT and green fluorescent protein (GFP) genes through the gametes of HD monkey. rHD-ESCs express mutant HTT and form intranuclear inclusion, a classical cellular feature of HD. Notably, mosaicism of the pathogenic polyQ region in the sperm as well as derived ESCs were also observed, consistent with intraindividual and intergenerational reports of mosaic CAG repeats [ 2 , 3 ]and CAG expansion in HD patients [ 4-7 ]. The confirmation of transgene inheritability and development of pathogenic HD phenotype in derived rHD-ESCs reported in this study is a milestone in the pursuit of a transgenic primate model with inherited mutant HTT for development of novel disease biomarkers and therapeutics.
authors.affiliation: Yerkes National Primate Research Center, Atlanta, Georgia, USA.
authors.forename: Kittiphong
authors.initials: K
authors.lastname: Putkhao
authors.forename: Jannet
authors.initials: J
authors.lastname: Kocerha
authors.forename: In-Ki
authors.initials: IK
authors.lastname: Cho
authors.forename: Jinjing
authors.initials: J
authors.lastname: Yang
authors.forename: Rangsun
authors.initials: R
authors.lastname: Parnpai
authors.forename: Anthony W S
authors.initials: AW
authors.lastname: Chan
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; C097188:polyglutamine