title: SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington's Disease Mice.
abstract: Huntington's disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 is a NAD+-dependent protein deacetylase that is implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested that the modulation of SIRT1 activity is neuroprotective in HD mouse models, however, the mechanisms controlling SIRT1 activity are unknown. We have identified a striatum-specific phosphorylation-dependent regulatory mechanism of SIRT1 induction under normal physiological conditions, which is impaired in HD. We demonstrate that SIRT1 activity is down-regulated in the brains of two complementary HD mouse models, which correlated with altered SIRT1 phosphorylation levels. This SIRT1 impairment could not be rescued by the ablation of DBC1, a negative regulator of SIRT1, but was linked to changes in the sub-cellular distribution of AMPK-α1, a positive regulator of SIRT1 function. This work provides insights into the regulation of SIRT1 activity with the potential for the development of novel therapeutic strategies.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Tulino
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Agnesska C
authors.initials: AC
authors.lastname: Benjamin
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Nelly
authors.initials: N
authors.lastname: Jolinon
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Smith
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Alisia
authors.initials: A
authors.lastname: Carnemolla
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C491992:BRINP1 protein, mouse; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1
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