Publication Date:
2008-05-20
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652570/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652570/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Shang-Hsun -- Cheng, Pei-Hsun -- Banta, Heather -- Piotrowska-Nitsche, Karolina -- Yang, Jin-Jing -- Cheng, Eric C H -- Snyder, Brooke -- Larkin, Katherine -- Liu, Jun -- Orkin, Jack -- Fang, Zhi-Hui -- Smith, Yoland -- Bachevalier, Jocelyne -- Zola, Stuart M -- Li, Shi-Hua -- Li, Xiao-Jiang -- Chan, Anthony W S -- R01 AG019206/AG/NIA NIH HHS/ -- R01 AG019206-07/AG/NIA NIH HHS/ -- R01 NS036232/NS/NINDS NIH HHS/ -- R01 NS036232-09/NS/NINDS NIH HHS/ -- R01 NS041669/NS/NINDS NIH HHS/ -- R01 NS041669-07/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Jun 12;453(7197):921-4. doi: 10.1038/nature06975. Epub 2008 May 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18488016" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Animals, Genetically Modified
;
Animals, Newborn
;
Brain/metabolism/pathology
;
Chorea/genetics/physiopathology
;
*Disease Models, Animal
;
Dystonia/genetics/physiopathology
;
Exons/genetics
;
Female
;
Humans
;
Huntington Disease/*genetics/metabolism/pathology/*physiopathology
;
Macaca mulatta/*genetics
;
Male
;
Nerve Tissue Proteins/*genetics/metabolism
;
Nuclear Proteins/*genetics/metabolism
;
Peptides/genetics/metabolism
;
Pregnancy
;
Survival Analysis
;
Trinucleotide Repeat Expansion/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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