HD Lighthouse Contributing Editor's Comment: As a major step towards treatments, HD researchers engineered mouse models of the disease by adding CAG repeats. Researchers Scott Zeitlin and Erin Clabough have now engineered a mouse without any CAG repeats in the region of the huntingtin's gene where excessive CAG repeats cause HD in people. The mice developed normally in utero unlike mice engineered to lack the huntingtin's gene altogether who die in utero. The huntingtin's protein is necessary for embryonic development, but the CAG repeats are not.

In adulthood, however, the CAG-depleted mice exhibited mild memory and learning deficits but actually performed better on the rotarod, a standard measure of motor performance, than normal mice.

The researchers suggest that the function of the CAG repeat is related to the regulation of energy within the cell. Examining cells in culture, they found that there were higher levels of ATP (adenosine triphosphate - cellular energy) present, but that the cells aged more quickly.

As RNA interference technologies improve and advance toward human clinical trials, it is important for researchers to learn all they can about the normal function of the huntingtin's protein and the role of the CAG repeats. This study shows that developing a technique to knock out the CAG regions in the normal and HD gene would not be a good therapeutic strategy.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 23 Jul 2006

Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular

Erin B.D. Clabough and Scott O. Zeitlin

Huntingtin (htt), the protein encoded by the Huntington's disease (HD) gene, contains a polymorphic stretch of glutamines (polyQ) near its N-terminus. When the polyQ stretch is expanded beyond 37Q, HD results. However, the role of the normal polyQ stretch in the function of htt is still unknown. To determine the contribution of the polyQ stretch to normal htt function, we have generated mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene (Hdh{Delta}Q). Hdh({Delta}Q/{Delta}Q) mice are born with normal Mendelian frequency and exhibit no gross phenotypic differences in comparison to control littermates, suggesting that the polyQ stretch is not essential for htt's functions during embryonic development. Adult mice, however, commit more errors initially in the Barnes circular maze learning and memory test and perform slightly better than wild-type controls in the accelerating rotarod test for motor coordination. To determine whether these phenotypes may reflect an altered cellular physiology in the Hdh{Delta}Q mice, we characterized the growth and energy status of primary embryonic and adult Hdh({Delta}Q/{Delta}Q) fibroblasts in culture. The Hdh{Delta}Q fibroblasts exhibited elevated levels of ATP, but senesced prematurely in comparison with wild-type fibroblasts. Taken altogether, these results suggest that htt's polyQ stretch is required for modulating longevity in culture and support the hypothesis that the polyQ stretch may also modulate a htt function involved in regulating energy homeostasis. # # #

Source: Human Molecular Genetics 2006 15(4):607-623

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