Huntington’s disease (HD) is a fatal neurodegenerative disorder for which there are no therapeutic treatments. Previous studies have suggested that an increase in SIRT1 activity might have a neuroprotective effect in mouse models of HD. SIRT1 is a NAD+-dependent protein deacetylase and plays an important role in neuronal health during development, differentiation and ageing. However, the mechanisms controlling SIRT1 activity and the effect of HD progression on such processes are currently unknown. In this study we explored the impact of HD on SIRT1 function in different brain regions of the R6/2 (fragment transgenic) and HdhQ150 (knock-in) HD mouse models. We show the existence of a striatum-specific age-dependent regulatory mechanism of SIRT1 activity and a down-regulation of SIRT1 function in the brains of both models. Interestingly, we did not detect a co-localization of SIRT1 with mHTT inclusions and to further support this finding, we did not observe any reduction of SIRT1 protein level in HD brains. In this study, we hypothesize that there is a link between SIRT1 activity and SIRT1 phosphorylation status and provide evidence of altered SIRT1 phosphorylation in the striatum and cerebellum of HD mice. DBC1 is a negative regulator of SIRT1. We found that the ablation of DBC1 did not improve behavioural impairments in R6/2 mice, suggesting that the mutant HTT-related reduction in SIRT1 activity might lie outside the inhibitory circuit controlled by DBC1. Taken together, these data show for the first time that there is a striatum-specific mechanism controlling SIRT1 activity via phosphorylation in an age-dependent manner and that the SIRT1 function is impaired in HD. This work provides insights into the mechanisms that regulate SIRT1 activity in the brain, confirms that SIRT1 plays a key role in both the normal and HD brain and opens new avenues for the development of therapeutic strategies.
DYSREGULATION OF SIRT1 ACTIVITY IN THE PATHOGENESIS OF HUNTINGTON’S DISEASE
Tulino, R. (Author). 2015
Student thesis: Doctoral Thesis › Doctor of Philosophy