Towards a transgenic model of Huntington's disease in a non-human primate

被引：336

作者：

Yang, Shang-Hsun ^{[1
,2
,3
]}

Cheng, Pei-Hsun ^{[1
,2
]}

Banta, Heather ^{[1
]}

Piotrowska-Nitsche, Karolina ^{[1
,2
,8
]}

Yang, Jin-Jing ^{[1
,2
]}

Cheng, Eric C. H. ^{[1
,2
]}

Snyder, Brooke ^{[1
,2
]}

Larkin, Katherine ^{[1
]}

Liu, Jun ^{[1
,2
,4
]}

Orkin, Jack ^{[1
]}

Fang, Zhi-Hui ^{[2
]}

Smith, Yoland ^{[1
,4
,5
]}

Bachevalier, Jocelyne ^{[1
,6
,7
]}

Zola, Stuart M. ^{[1
,4
,7
,9
]}

Li, Shi-Hua ^{[2
]}

Li, Xiao-Jiang ^{[2
,3
,4
]}

Chan, Anthony W. S. ^{[1
,2
,3
,4
]}

机构：

[1] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA

[2] Emory Univ, Dept Human Genet, Atlanta, GA 30329 USA

[3] Emory Univ, Genet & Mol Biol Program, Atlanta, GA 30329 USA

[4] Emory Univ, Neurosci Program, Atlanta, GA 30329 USA

[5] Emory Univ, Dept Neurol, Atlanta, GA 30329 USA

[6] Emory Univ, Dept Psychol, Atlanta, GA 30329 USA

[7] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30329 USA

[8] Polish Acad Sci, Dept Expt Embryol, Inst Genet & Anim Breeding, PL-05552 Wolka Kosowska, Poland

[9] Vet Affairs Med Ctr, Atlanta, GA 30033 USA

来源：

NATURE | 2008年 / 453卷 / 7197期

关键词：

D O I：

10.1038/nature06975

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1-4). 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(5). Mutant HTT with expanded polyglutamine ( polyQ) is widely expressed in the brain and peripheral tissues(2,6), 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(7), neurological and genetic similarities(8,9) between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases(10,11). 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.

引用

页码：921 / U56

页数：5

共 21 条

[1] Polyglutamine expansion and Huntington's disease [J].