当前位置:生物帮 > 国内研究 > 植物学 > 正文

J Neurosci:中科院生物物理所陈畅课题组发现调控“年老忘事”新靶点GSNOR

相关专题:
摘要 : 2017年9月7日,国际著名神经科学学术期刊《The Journal of Neuroscience》杂志上在线发表了中国科学院生物物理所陈畅课题组题为“Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα”的研究论文。

2017年9月7日,国际著名神经科学学术期刊《The Journal of Neuroscience》杂志上在线发表了中国科学院生物物理所陈畅课题组题为“Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα”的研究论文。论文首次揭示亚硝基化谷胱甘肽还原酶GSNOR(S-nitrosoglutathione reductase)在衰老相关认知功能损伤中的关键作用。陈畅课题组博士后张玉英为本文的第一作者,陈畅研究员为本文的通讯作者。

随着世界人口老龄化问题的加剧,脑老化以及神经退行性疾病带给人们的威胁越来越大。美国 Marist 民意调查机构在1247名成年人对于衰老的恐惧调查显示,对比容颜消逝以及多种退行性疾病,82%的民众认为衰老相关的认知功能损伤对他们来说是衰老带来的最大恐惧。衰老相关的认知功能损伤确实严重降低了老年人的生活质量和自主生活能力,并且给家庭和社会带来了巨大的看护压力和经济负担,所以研究衰老相关的认知功能损伤机制并寻找应对策略有重大意义。

陈畅课题组研究发现,在衰老人群和小鼠的海马组织中GSNOR的表达水平随年龄显著增加。神经元特异性高表达GSNOR的转基因小鼠学习记忆能力明显缺陷,海马脑片长时程增强损伤以及海马神经元树突棘密度降低。在自然衰老小鼠(22月龄)中敲除GSNOR可以增强衰老小鼠的认知功能以及海马脑片长时程增强作用。进一步通过亚硝基化修饰定量蛋白质组学分析自然衰老小鼠海马中亚硝基化修饰水平的变化,发现认知功能关键蛋白CaMKIIα的亚硝基化修饰水平在衰老海马中明显降低。我们在海马神经元中确定了GSNOR对于CaMKIIα的亚硝基化修饰水平的调控以及GSNOR可以通过降低海马区CaMKIIα的亚硝基化修饰下调其在突触小体中的积累,同时抑制下游谷氨酸受体GLUR1(S831)磷酸化修饰。另外,实验证明通过补充NO信号通路可以挽回神经元特异性高表达GSNOR诱导的学习记忆损伤。

研究结果确定了 GSNOR 是衰老相关认知功能损伤的新的潜在靶点,并且与传统的自由基衰老学说相反,提出 NO 信号通路不足很可能是导致衰老相关认知功能损伤的重要原因。同时,研究还在体内首次证明了CaMKIIα的亚硝基化修饰的新机制,GSNOR 可以通过下调 CaMKIIα的亚硝基化修饰抑制其在突触小体中的积累。这些结果为减缓衰老相关认知功能损伤提供了潜在的新靶点和新策略。

J Neurosci:中科院生物物理所陈畅课题组发现调控“年老忘事”新靶点GSNOR
图示:小鼠海马高表达GSNOR诱导衰老相关认知功能损伤及机制

原文链接:

Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKIIα

原文摘要:

As the population ages, an increasing number of people suffer from age-related cognitive impairment. However, the mechanisms underlying this process remain unclear. Here, we found that S-nitrosoglutathione reductase (GSNOR), the key enzyme that metabolizes intracellular nitric oxide (NO) and regulates S-nitrosation, was significantly increased in the hippocampus of both aging humans and mice. Transgenic mice overexpressing GSNOR exclusively in neurons showed cognitive impairment in behavioral tests, including the Morris water maze, fear conditioning and the Y-maze test. We also found that GSNOR transgenic mice have long-term potentiation (LTP) defects and lower dendrite spine density, while GSNOR knock-out mice rescued the age-related cognitive impairment. Analysis of S-nitrosation showed significantly decreased hippocampal CaMKIIα S-nitrosation in naturally aged mice and GSNOR transgenic mice. Consistent with the change in CaMKIIα S-nitrosation, the accumulation of CaMKIIα in the hippocampal synaptosomal fraction, as well as its downstream signaling targets p (S831)-GLUR1, was also significantly decreased. All these effects could be rescued in the GSNOR knock-out mice. We further verified that the S-nitrosation of CaMKIIα was responsible for the CaMKIIα synaptosomal accumulation by mutating CaMKIIα S-nitrosated sites (C280/289). Up-regulation of the NO signaling pathway rescued the cognitive impairment in GSNOR transgenic mice. In summary, our research demonstrates that GSNOR impairs cognitive function in aging and it could serve as a new potential target for the treatment of age-related cognitive impairment. In contrast to the free radical theory of aging, NO signaling deficiency may be the main mediator of age-related cognitive impairment.

DOI:10.1523/JNEUROSCI.0681-17.2017

作者:陈畅 点击:

    热门文章TOP