SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis
SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis
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DOI：
10.1038/sj.emboj.7601758
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发表时间：
2007-07-11
期刊：
影响因子：
11.4
通讯作者：
Tsai, Li-Huei
中科院分区：
文献类型：
--
作者：
Kim, Dohoon;Nguyen, Minh Dang;Tsai, Li-Huei
随着年龄的增长，神经元的逐渐丧失是各种衰弱性神经系统疾病的基础，包括阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS），但目前几乎没有有效的治疗方法。SIR 2基因促进多种生物体的长寿，并可能是热量限制的健康益处的基础，热量限制是一种延缓哺乳动物衰老和神经退化的饮食。在这里，我们报告说，SIR 2，SIRT 1的人类同源物，在AD，ALS的小鼠模型和神经毒性损伤的原代神经元中上调。在AD/tau蛋白病和ALS的细胞模型中，SIRT 1和白藜芦醇（SIRT 1激活分子）都能促进神经元存活。在诱导型p25转基因小鼠中，一种AD和tau蛋白病模型，白藜芦醇减少了海马中的神经变性，防止了学习障碍，并降低了已知SIRT 1底物PGC-1 α和p53的乙酰化。此外，在p25转基因小鼠的海马中注射SIRT 1慢病毒赋予了对神经变性的显著保护。因此，SIRT 1构成了衰老和人类神经退行性疾病之间的独特分子联系，并为治疗干预提供了有前途的途径。
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.