Overexpressing Normal Huntington's Slightly Beneficial in a Mouse Model

HD Lighthouse Contributing Editor's Comment: The normal huntingtin's protein (which scientists call 'wild type') is necessary for embryonic development and neuronal survival. In mice, even a 50 percent reduction in huntingtin's results in neurological deficits.

In this study, Van Raamsdonk and colleagues crossed the YAC128 mouse (a mouse model of HD) with a the YAC18 mouse which overproduces normal huntingtin's to see if normal huntingtin's could act as a treatment for Huntington's Disease. An earlier study had shown that the YAC18 mice had some protection against a neurotoxin sometimes used to model Huntington's Disease.

In mice and men, both copies of the huntingtin gene express themselves. In these mice, the HD gene causes the regular amount of the mutated protein to be produced and the other gene causes extra amounts of the normal protein to be produced.

While they found that there was somewhat less neuropathology in the YAC128/18 mice than in the regular YAC128, there were no differences in performances on either the rotarod test or the open field test and both types lost the same amount of volume in the striatum. The study did not go on long enough or include enough mice to detect any potential differences in survival time but there didn't appear to be a trend to that effect.

The study suggests that while not having enough of the normal huntingtin's may cause some neurological pathology which can be remedied by increasing the amount, overexpressing it is not enough to counteract the negative effects of the HD protein.

To read the full article, click here: http://www.biomedcentral.com/content/pdf/1471-2202-7-80.pdf

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 09 Dec 2006

Background

Huntington disease (HD) is an adult onset neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. Htt function is essential for embryonic survival as well as normal function during the postnatal period. In addition to having roles in transcription and transport, recent evidence demonstrates that wild-type htt is neuroprotective in vivo. To determine whether treatment with wild-type htt would be beneficial in HD, we crossed the YAC128 mouse model of HD with mice that over-express wild-type htt (YAC18 mice) to generate YAC128 mice that over-express wild-type htt (YAC18/128 mice).

Results

YAC18/128 mice were found to express mutant htt at the same level as YAC128 mice and wild-type htt at the same level as YAC18 mice. YAC18/128 mice show no significant behavioural improvement compared to YAC128 mice in the rotarod test of motor coordination or in an automated open field test. In the brain, YAC18/128 mice show no significant improvement in striatal volume, striatal neuronal numbers or striatal DARPP-32 expression compared to YAC128 mice. In contrast, striatal neuronal cross-sectional area showed significant improvement in YAC18/128 mice compared to YAC128 mice.

Conclusions

While the over-expression of wild-type htt results in a mild improvement in striatal neuropathology in YAC128 mice, our findings suggest that treatment with wild-type htt may not be sufficient to ameliorate the symptoms of HD in this model.

Source: BMC Neuroscience 2006 Dec 5;7(1):80 [Epub ahead of print]

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