Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture.
Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture.
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DOI：
10.1371/journal.pone.0014731
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发表时间：
2011-03-01
期刊：
影响因子：
3.7
通讯作者：
Alano CC
中科院分区：
文献类型：
--
作者：
Kim SH;Lu HF;Alano CC
Sirtuins（Sirt）是一个依赖于烟酰胺腺嘌呤核苷酸（NAD）的脱乙酰酶家族，与能量代谢和寿命有关。在已知的Sirt同工型（Sirt 1 -7）中，Sirt 3被鉴定为应激响应性脱乙酰酶，最近显示其在应激条件下保护细胞中起作用。在这里，我们证明了Sirt 3在神经元中的存在，并表征了Sirt 3在NMDA诱导的兴奋性毒性下神经元存活中的作用。为了诱导兴奋性毒性损伤，我们将原代培养的小鼠皮层神经元暴露于NMDA（30 µM）。NMDA通过激活多聚腺苷二磷酸核糖聚合酶-1（PARP-1）诱导神经元胞质NAD（而非线粒体NAD）迅速减少。线粒体Sirt 3在PARP-1介导的NAD耗竭后增加，这可通过抑制PARP-1或外源性NAD逆转。我们发现，大量的活性氧（ROS）在这种NAD耗尽的条件下产生介导的线粒体Sirt 3的增加。通过用Sirt 3过表达质粒或Sirt 3 siRNA转染原代神经元，我们发现Sirt 3是神经保护免受兴奋性毒性所必需的。这项研究首次证明了线粒体Sirt 3作为一种促生存因子，在保护兴奋性毒性损伤下的神经元方面发挥重要作用。
Sirtuins (Sirt), a family of nicotinamide adenine nucleotide (NAD) dependent deacetylases, are implicated in energy metabolism and life span. Among the known Sirt isoforms (Sirt1-7), Sirt3 was identified as a stress responsive deacetylase recently shown to play a role in protecting cells under stress conditions. Here, we demonstrated the presence of Sirt3 in neurons, and characterized the role of Sirt3 in neuron survival under NMDA-induced excitotoxicity. To induce excitotoxic injury, we exposed primary cultured mouse cortical neurons to NMDA (30 µM). NMDA induced a rapid decrease of cytoplasmic NAD (but not mitochondrial NAD) in neurons through poly (ADP-ribose) polymerase-1 (PARP-1) activation. Mitochondrial Sirt3 was increased following PARP-1 mediated NAD depletion, which was reversed by either inhibition of PARP-1 or exogenous NAD. We found that massive reactive oxygen species (ROS) produced under this NAD depleted condition mediated the increase in mitochondrial Sirt3. By transfecting primary neurons with a Sirt3 overexpressing plasmid or Sirt3 siRNA, we showed that Sirt3 is required for neuroprotection against excitotoxicity. This study demonstrated for the first time that mitochondrial Sirt3 acts as a prosurvival factor playing an essential role to protect neurons under excitotoxic injury.
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影响因子：
5.5
作者：
Duan, Yuntao;Gross, Robert A.;Sheu, Shey-Shing
通讯作者：
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影响因子：
30.8
作者：
Guarente, L
通讯作者：
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DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.