@article{0fda54748e904d6da3f805ce22cb8bd0,
title = "SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease",
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.",
keywords = "BDNF, huntingtin, hypocretin, hypothalamus, MCH, orexin, Sirtuin",
author = "B. Baldo and S. Gabery and R. Soylu-Kucharz and Cheong, {R. Y.} and Henningsen, {J. B.} and E. Englund and C. McLean and D. Kirik and G. Halliday and {\AA}. Peters{\'e}n",
note = "Funding Information: We thank Ulla Samuelsson, Anneli Josefsson and Anna Hans{\'e}n for excellent technical assistance. Tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales. Tissues were also received from the Victorian Brain Bank Network, supported by the Mental Health Research Institute, Alfred Hospital, Victorian Forensic Institute of Medicine, The University of Melbourne, Helen Macpherson Smith Trust, Parkinson{\textquoteright}s Victoria and Perpetual Philanthropic Service. This work was supported by grants from the Swedish Medical Research Council to{\textcopyright}A.P. (grant numbers 2010-4500 and 2013-3537) and D.K. (grant numbers 2008-3092 and 2012-5854); the Ragnar So€derberg Foundation to{\textcopyright}A.P.; the Province of Sk{\textcopyright}ane State Grants (ALF) to{\textcopyright}A.P.; Neuro Sweden Foundation (Neuroforbundet) to{\textcopyright}A.P.; the Royal Physiographic Society to S.G. GMH is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (#1079679). Funding Information: We thank Ulla Samuelsson, Anneli Josefsson and Anna Hans{\'e}n for excellent technical assistance. Tissues were received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales. Tissues were also received from the Victorian Brain Bank Network, supported by the Mental Health Research Institute, Alfred Hospital, Victorian Forensic Institute of Medicine, The University of Melbourne, Helen Macpherson Smith Trust, Parkinson's Victoria and Perpetual Philanthropic Service. This work was supported by grants from the Swedish Medical Research Council to {\AA}.P. (grant numbers 2010-4500 and 2013-3537) and D.K. (grant numbers 2008-3092 and 2012-5854); the Ragnar S{\"o}derberg Foundation to {\AA}.P.; the Province of Sk{\aa}ne State Grants (ALF) to {\AA}.P.; Neuro Sweden Foundation (Neurof{\"o}rbundet) to {\AA}.P.; the Royal Physiographic Society to S.G. GMH is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (#1079679). Publisher Copyright: {\textcopyright} 2018 British Neuropathological Society",
year = "2019",
month = jun,
doi = "10.1111/nan.12514",
language = "English",
volume = "45",
pages = "361--379",
journal = "Neuropathology and Applied Neurobiology",
issn = "0305-1846",
publisher = "Wiley-Blackwell",
number = "4",
}