SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease

Research output: Contribution to journalArticle

Abstract

Aims: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. Methods: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. Results: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively 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 and reduced mRNA levels of orexin (hypocretin), prodynorphin 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 HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. Conclusions: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

Details

Authors
Organisations
External organisations
  • Alfred Hospital
  • University of Sydney
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • BDNF, huntingtin, hypocretin, hypothalamus, MCH, orexin, Sirtuin
Original languageEnglish
Pages (from-to)361-379
JournalNeuropathology and Applied Neurobiology
Volume45
Issue number4
Early online date2018 Jul 18
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes