SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington's Disease Mice

TY - JOUR

T1 - SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington's Disease Mice

AU - Tulino, Raffaella

AU - Benjamin, Agnesska C

AU - Jolinon, Nelly

AU - Smith, Donna L

AU - Chini, Eduardo N

AU - Carnemolla, Alisia

AU - Bates, Gillian P

PY - 2016/1/27

Y1 - 2016/1/27

N2 - 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.

AB - 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.

KW - AMP-Activated Protein Kinases

KW - Animals

KW - Brain

KW - Cerebellum

KW - Corpus Striatum

KW - Disease Models, Animal

KW - Female

KW - Huntington Disease

KW - Immunohistochemistry

KW - Immunoprecipitation

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred CBA

KW - Mice, Knockout

KW - Nerve Tissue Proteins

KW - Phenotype

KW - Phosphorylation

KW - Serotonin Plasma Membrane Transport Proteins

KW - Sirtuin 1

U2 - 10.1371/journal.pone.0145425

DO - 10.1371/journal.pone.0145425

M3 - Article

C2 - 26815359

SN - 1932-6203

VL - 11

JO - PLoS ONE

JF - PLoS ONE

IS - 1

M1 - e0145425

ER -