Abstract
Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients.
Highlights
Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene
We showed that genetic knockdown of S6k1 had no beneficial effect on the levels of aggregated mutant huntingtin (mHTT) or on any of the behavioural or physiological deficits observed in the R6/2 mouse model, indicating that inhibition of S6 kinase 1 (S6K1) is unlikely to be of benefit in the treatment of HD
In order to investigate whether deletion of S6k1 could ameliorate the pathogenesis of HD, we used a genetic approach to delete S6k1 in the R6/2 mouse model of HD
Summary
Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. No improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels These results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients. An inhibitor of the key nutrient signal integrating protein mTORC, attenuated mHTT accumulation and cell death in cell culture models of HD, and protected against degeneration of photoreceptor neurons in a fly overexpressing 120-CAG repeat huntingtin in the eye[24]. MHTT enhanced mTORC1 activity, which in turn is thought to contribute to the pathogenesis of HD
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