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.
N1 - Publisher Copyright:
© 2016 Tulino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Huntington's disease (HD) is a neurodegenerative disorder for which there are no diseasemodifying 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 striatumspecific 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 diseasemodifying 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 striatumspecific 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.
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U2 - 10.1371/journal.pone.0145425
DO - 10.1371/journal.pone.0145425
M3 - Article
C2 - 26815359
AN - SCOPUS:84958211408
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 1
M1 - e0145425
ER -