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 symptoms1,2,3,4. 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) gene5. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues2,6, 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 physiological7, neurological and genetic similarities8,9 between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases10,11. 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.

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Figure 1: Generation of a transgenic model in monkeys of HD.
Figure 2: Expression of mutant HTT in HD monkey peripheral tissues and brains.
Figure 3: Histopathology of HD monkey brain.

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Acknowledgements

We thank J. Fanton (deceased), M. Zelinski-Wooten, M. Sparman and D. Wolf for consultation, C. Lois for lentivirus backbone and C. Testa for critical review of the manuscript. We also thank F. Zhang, T. Caspary, S. Warren, J. Greene, T. Wichmann, M. Wilson, S. Chikazawa, K. Gould, L. Walker, K. Layug, E. Strobert, J. Else, J. Ksiazek, K. Strait, F. Stroud, J. Jenkins, J. Cohen, J. Pare, S. Jenkins, K. Paul, S. Lackey, J. Johnson-Ward, the veterinary staff, the animal resource and the endocrine core laboratory at the Yerkes National Primate Research Center. Acryline was provided by NICHD/NIH. All transgenic HD monkeys were housed under the guideline of the IACUC approved procedures and the support of YNPRC Division of Animal Resources. All newborn monkeys were closely monitored by the veterinary staff and infant care personnel. All procedures were approved by YNPRC/Emory Animal Care and Biosafety Committees. The YNPRC is supported by NIH/NCRR. A.W.S.C., S.H.L. and X.J.-L are supported by grants awarded by the NIH.

Author Contributions S.-H.Y. carried out assisted reproductive technique (ART) in monkeys, viral gene transfer, construct design and molecular analysis; P.-H.C., construct design and evaluation; K.P.-N., ART in monkeys; H.B., animal management; behavioural testing and all animal procedures; K.L., animal care and behavioural testing; E.C.H.C., molecular analysis; J.-J.Y., preparation of high titre lentiviruses; B.S., J.L. and Z.H.F., neuropathological analysis; J.O., surgical procedures and animal care; Y.S., neuropathological analysis; J.B., design of behavioural and cognitive testing; S.M.Z., experimental design and manuscript preparation; S.H.L. and X.J.-L., construct design, analysis and manuscript preparation; A.W.S.C., ART in monkey, viral gene transfer, experimental design, construct design, molecular analysis and manuscript preparation.

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Correspondence to Anthony W. S. Chan.

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Yang, S., Cheng, P., Banta, H. et al. Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453, 921–924 (2008). https://doi.org/10.1038/nature06975

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