PMID- 30019499
OWN - NLM
STAT- MEDLINE
DCOM- 20200821
LR  - 20200821
IS  - 1365-2990 (Electronic)
IS  - 0305-1846 (Linking)
VI  - 45
IP  - 4
DP  - 2019 Jun
TI  - SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways 
      are altered in Huntington disease.
PG  - 361-379
LID - 10.1111/nan.12514 [doi]
AB  - 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.
CI  - (c) 2018 British Neuropathological Society.
FAU - Baldo, B
AU  - Baldo B
AD  - Translational Neuroendocrine Research Unit, Department of Experimental Medical 
      Science, Lund University, Lund, Sweden.
FAU - Gabery, S
AU  - Gabery S
AD  - Translational Neuroendocrine Research Unit, Department of Experimental Medical 
      Science, Lund University, Lund, Sweden.
FAU - Soylu-Kucharz, R
AU  - Soylu-Kucharz R
AD  - Translational Neuroendocrine Research Unit, Department of Experimental Medical 
      Science, Lund University, Lund, Sweden.
FAU - Cheong, R Y
AU  - Cheong RY
AD  - Translational Neuroendocrine Research Unit, Department of Experimental Medical 
      Science, Lund University, Lund, Sweden.
FAU - Henningsen, J B
AU  - Henningsen JB
AD  - Translational Neuroendocrine Research Unit, Department of Experimental Medical 
      Science, Lund University, Lund, Sweden.
FAU - Englund, E
AU  - Englund E
AD  - Division of Oncology and Pathology, Department of Clinical Sciences, Lund 
      University, Lund, Sweden.
FAU - McLean, C
AU  - McLean C
AD  - Department of Pathology, Alfred Hospital, Melbourne, Vic, Australia.
FAU - Kirik, D
AU  - Kirik D
AD  - B.R.A.I.N.S. Unit, Department of Experimental Medical Science, Lund University, 
      Lund, Sweden.
FAU - Halliday, G
AU  - Halliday G
AUID- ORCID: 0000-0003-0422-8398
AD  - Brain and Mind Centre, Sydney Medical School, UNSW Medicine and NeuRA, The 
      University of Sydney, Sydney, NSW, Australia.
FAU - Petersen, A
AU  - Petersen A
AUID- ORCID: 0000-0001-5488-1200
AD  - Translational Neuroendocrine Research Unit, Department of Experimental Medical 
      Science, Lund University, Lund, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180829
PL  - England
TA  - Neuropathol Appl Neurobiol
JT  - Neuropathology and applied neurobiology
JID - 7609829
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - Aged
MH  - Brain/*metabolism
MH  - Female
MH  - Humans
MH  - Huntington Disease/*metabolism
MH  - Hypothalamus/*metabolism
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Male
MH  - Middle Aged
MH  - Nerve Tissue Proteins/metabolism
MH  - Neurons/pathology
MH  - Sirtuin 1/*metabolism
OTO - NOTNLM
OT  - BDNF
OT  - MCH
OT  - Sirtuin
OT  - huntingtin
OT  - hypocretin
OT  - hypothalamus
OT  - orexin
EDAT- 2018/07/19 06:00
MHDA- 2020/08/22 06:00
CRDT- 2018/07/19 06:00
PHST- 2018/03/02 00:00 [received]
PHST- 2018/07/11 00:00 [accepted]
PHST- 2018/07/19 06:00 [pubmed]
PHST- 2020/08/22 06:00 [medline]
PHST- 2018/07/19 06:00 [entrez]
AID - 10.1111/nan.12514 [doi]
PST - ppublish
SO  - Neuropathol Appl Neurobiol. 2019 Jun;45(4):361-379. doi: 10.1111/nan.12514. Epub 
      2018 Aug 29.