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 senescence in vitro

Abstract

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(DeltaQ)). Hdh(DeltaQ/DeltaQ) 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(DeltaQ) mice, we characterized the growth and energy status of primary embryonic and adult Hdh(DeltaQ/DeltaQ) fibroblasts in culture. The Hdh(DeltaQ) 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.

Ameliorating Huntington's Disease by Targeting Huntingtin mRNA

“…Whether accumulation of these aggregates is neurotoxic or neuroprotective is still under debate since evidence also suggests that soluble mutant htt is the main toxic component (Davies et al, 1997;Saudou et al, 1998;Arrasate et al, 2004). While the expanded polyQ repeat displays pathogenic properties it is probably not essential for normal function (Clabough & Zeitlin, 2006). Mutant htt is more disposed to proteolysis and it was shown that small N-terminal htt fragments are more toxic than full length mutant htt (Cooper et al, 1998).…”

Structure/Function Analysis of the Huntingtin N-terminus Encoded by Htt Exon 1 Using Knock-In Mouse Models

“…1-4) [110]. These results suggest that enhancing selective macroautophagy may be beneficial for organisms in general, not only in the context of disease [109,110]. ER stress and autophagy regulation are closely interconnected.…”

“…The Htt polyQ stretch does not appear to contribute to its essential functions, as its deletion in mice does not perturb embryonic development or result in motor or neuropathological deficits in adults [109]. Deletion of the polyQ stretch resulted in improved motor coordination, and a significantly increased lifespan [109,110].…”

“…Deletion of the polyQ stretch resulted in improved motor coordination, and a significantly increased lifespan [109,110].…”

“…3-3C). Targeted ES cell clones (3 per gene targeting construct) were injected into 3.5 day old C57BL/6J blastocysts to generate chimeric mice ( does not result in embryonic lethality, it is not unexpected that a combined deletion of the polyQ and PRR domains also does not impact embryonic development [61,109].…”