Monkey model for Huntington disease

Written byAndrea Gawrylewski

| 2 min read

Scientists have created the first transgenic monkey model of Huntington disease (HD), according to a linkurl:report;http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature06975.html that appeared yesterday in Nature. But it's unclear how closely the model represents the disease in humans. The study, led by Anthony Chan, at the Yerkes National Primate Research Center, successfully bred five rhesus macaques with the repeated amino acid sequence CAG in the human huntingtin gene -- the telltale genetic defect in HD. The group injected lentiviruses expressing 84 repeated sequences and green fluorescent protein (GFP) into 130 monkey oocytes, of which five developed into embryos and were born. Two monkeys died within one day of being born, two lived one week and one month, respectively. The last monkey appeared to have a normal phenotype. The two monkeys that survived past the first day displayed Huntington-like symptoms such as motor impairment and chorea. The next step will be to create a later-onset model of the disease and fine-tune the method, Chan told The Scientist. In 2001 Chan, then at Oregon National Primate Research Center, linkurl:reported;http://www.the-scientist.com/article/display/19383/ inserting GFP into the monkey genome, demonstrating that it was possible to create primate transgenic animals. In addition to creating a primate model for a specific disease, this new study also showed that more than one gene can be inserted into a primate genome, opening up the possibility of using the technique to model other diseases with less straightforward pathologies. How well this model resembles the human presentation of HD, however, is still up for debate. "There is no doubt that overexpressing [CAG] is toxic, as shown in mouse models and now in a non-human primate model," linkurl:Vanessa Wheeler,;http://www.mgh.harvard.edu/chgr/faculty_wheeler.htm from Harvard Medical School, wrote in an Email to The Scientist. "The question to my mind, is whether the process that mediates this toxicity is the same as the process that causes HD." In human patients, the expanded region of repeat CAG nucleotides initiates the pathogenic process that results in HD and the production of huntingtin, a large 350 kDa protein. But Chan's technique of inserting repeats into the monkey huntingtin gene resulted in a tiny fragment of the huntingtin protein, said Wheeler, which would not necessarily be responsible for the Huntington pathology. Also, she added,the toxicity of the 84 repeated sequences Chan inserted was much higher than the level of toxicity that would be expected from that number of repeats in human patients, suggesting that the method of the experiment itself may have led to the observed early onset and mortality of the monkeys. "So, my feeling is that the model as it stands is not really going to allow us to get at the question of how (full-length) mutant huntingtin causes HD," Wheeler said.

Monkey model for Huntington disease

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