SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

被引:872
作者
Kim, Dohoon
Nguyen, Minh Dang
Dobbin, Matthew M.
Fischer, Andre
Sananbenesi, Farahnaz
Rodgers, Joseph T.
Delalle, Ivana
Baur, Joseph A.
Sui, Guangchao
Armour, Sean M.
Puigserver, Pere
Sinclair, David A.
Tsai, Li-Huei
机构
[1] MIT, Tsai Brain & Cognit Sci, Boston, MA 02139 USA
[2] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA
[3] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada
[4] Univ Gottingen, Sch Med, Max Planck Soc, D-3400 Gottingen, Germany
[5] MIT, RIKEN, Neurosci Res Ctr, Howard Hughes Med Inst,Dept Brain & Cognit Sci, Boston, MA USA
[6] Harvard Univ, Sch Med, Div Med Sci, Boston, MA USA
[7] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[8] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Cell Biol, Boston, MA USA
[9] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Boston, MA USA
关键词
AD; ALS; neurodegeneration; p25; SIRT1;
D O I
10.1038/sj.emboj.7601758
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.
引用
收藏
页码:3169 / 3179
页数:11
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