A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease.

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD.

The Nova Scotia Community Cancer Matrix: A geospatial tool to support cancer prevention.

Globally, cancer is a leading cause of death and morbidity and its burden is increasing worldwide. It is established that medical approaches alone will not solve this cancer crisis. Moreover, while cancer treatment can be effective, it is costly and access to treatment and health care is vastly inequitable. However, almost 50% of cancers are caused by potentially avoidable risk factors and are thus preventable. Cancer prevention represents the most cost-effective, feasible and sustainable pathway towards global cancer control. While much is known about cancer risk factors, prevention programs often lack consideration of how place impacts cancer risk over time. Maximizing cancer prevention investment requires an understanding of the geographic context for why some people develop cancer while others do not. Data on how community and individual level risk factors interact is therefore required. The Nova Scotia Community Cancer Matrix (NS-Matrix) study was established in Nova Scotia (NS), a small province in Eastern Canada with a population of 1 million. The study integrates small-area profiles of cancer incidence with cancer risk factors and socioeconomic conditions, to inform locally relevant and equitable cancer prevention strategies. The NS-Matrix Study includes over 99,000 incident cancers diagnosed in NS between 2001 and 2017, georeferenced to small-area communities. In this analysis we used Bayesian inference to identify communities with high and low risk for lung and bladder cancer: two highly preventable cancers with rates in NS exceeding the Canadian average, and for which key risk factors are high. We report significant spatial heterogeneity in lung and bladder cancer risk. The identification of spatial disparities relating to a community's socioeconomic profile and other spatially varying factors, such as environmental exposures, can inform prevention. Adopting Bayesian spatial analysis methods and utilizing high quality cancer registry data provides a model to support geographically-focused cancer prevention efforts, tailored to local community needs.

Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity.

Huntingtin (Htt) is a widely expressed protein that causes tissue-specific degeneration when mutated to contain an expanded polyglutamine (poly(Q)) domain. Although Htt is large, 350 kDa, the appearance of amino-terminal fragments of Htt in extracts of postmortem brain tissue from patients with Huntington disease (HD), and the fact that an amino-terminal fragment, Htt exon 1 protein (Httex1p), is sufficient to cause disease in models of HD, points to the importance of the amino-terminal region of Htt in the disease process. The first exon of Htt encodes 17 amino acids followed by a poly(Q) repeat of variable length and culminating with a proline-rich domain of 50 amino acids. Because modifications to this fragment have the potential to directly affect pathogenesis in several ways, we have surveyed this fragment for potential post-translational modifications that might affect Htt behavior and detected several modifications of Httex1p. Here we report that the most prevalent modifications of Httex1p are NH(2)-terminal acetylation and phosphorylation of threonine 3 (pThr-3). We demonstrate that pThr-3 occurs on full-length Htt in vivo, and that this modification affects the aggregation and pathogenic properties of Htt. Thus, therapeutic strategies that modulate these events could in turn affect Htt pathogenesis.