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

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Abstract
Huntington's disease is a severely disabling and lethal neurodegenerative disorder. The development of a non-human primate model for the disease would be invaluable in understanding its pathology and in developing therapeutic strategies, and this paper reports a significant step towards that goal is reported in this issue. Transgenic rhesus macaque monkeys that express the first exon of the polyglutamine-expanded human huntingtin gene develop key features of Huntington's disease, including dystonia and chorea. The data suggest that it will be feasible to generate non-human primate models for Huntington's disease and possibly for other neurodegenerative disorders, where rodent models may not reflect the brain changes and behavioural features of the human disease. 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.