A52 SIRT1 is increased in affected brain regions in huntington disease impacting hypothalamic metabolic pathways

Abstract

Background Metabolic dysfunction is part of the neurodegenerative Huntington disease (HD) and may be involved in modulating the disease process. The underlying mechanisms are not known. The metabolic regulators sirtuins have been suggested to play a role in HD but the published results are conflicting. It is not known to what extent sirtuins are affected in different brain regions in HD. Aims Metabolic dysfunction is involved in modulating the disease process in HD but the underlying mechanisms are not known. We aimed at investigating whether or not the metabolic regulators sirtuins are affected in HD. Methods qRT-PCR and immunohistochemistry were used to assess levels of SIRT1–3 and downstream targets in postmortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin using recombinant adeno-associated viral vectors in mice. Results We show that mRNA levels of the metabolic regulator SIRT1 are upregulated in the striatum and the cerebral cortex in postmortem HD brain but not in the less affected cerebellum in postmortem HD brain. Levels of SIRT2 are only upregulated in the striatum and SIRT3 is not affected in HD. Interestingly, both mRNA and protein levels of SIRT1 were increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets as well as downregulation of the neuropeptides orexin (hypocretin), dynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant huntingtin suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes of SIRT1 require more widespread expression of mutant huntingtin. Conclusions We show that SIRT1 expression is increased in HD affected brain regions, impacting metabolic pathways in specific nuclei of the hypothalamus in HD.