大脑中产生的气体分子一氧化氮能够对神经元造成损伤.当大脑产生太多一氧化氮时,它导致中风和诸如阿尔茨海默病之类的神经退化性疾病加重和恶化.在一项新的研究中,来自美国桑福德-伯纳姆医学研究所(Sanford-Burnham Medical Research Institute)发现一氧化氮不仅对神经元造成损伤,而且它也关闭大脑修复机制.相关研究结果于2013年2月4日在线发表在PNAS期刊上,论文标题为"S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke".
论文通信作者Stuart A. Lipton,博士说,"在这项研究中,我们发现关于在多种疾病中大脑内自然化学反应如何能够导致大脑损伤---记忆和认知功能丧失---的新线索."这项发现提示着如果人们能够找到一种方法来逆转一氧化氮对神经元中特定酶的影响,那么就可能能够开发新的策略来治疗中风和其他疾病.
学习和记忆部分上受到大脑中NMDA谷氨酸受体的控制.这些受体与神经细胞膜上调节钙离子和钠离子进出神经元的孔相结合.当这些NMDA受体遭受过度激活时,它们触发一氧化氮产生.接着,一氧化氮通过S-亚硝基化(S-nitrosylation)反应附着到其他的蛋白上.当这些S-亚硝基化的蛋白参与细胞存活和寿命时,一氧化氮能够导致脑细胞提前死亡,而脑细胞提前死亡是神经退化性疾病的一个特征.
在这项研究中,研究人员利用体外培养的神经元和活的中风模式小鼠来研究一氧化氮与协助修复神经元损伤的蛋白之间的关系.他们发现一氧化氮与酶SHP-2发生反应来抑制保护性的被称作ERK1/2信号通路的分子级联事件.因此,一氧化氮不仅对神经元造成损伤,而且它也阻断大脑进行自我修复的能力。
DOI:10.1073/pnas.1215501110
PMC:
PMID:
S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke
Zhong-Qing Shia, Carmen R. Sunicoa, Scott R. McKerchera, Jiankun Cuia, Gen-Sheng Fengb, Tomohiro Nakamuraa, and Stuart A. Liptona,1
Overproduction of nitric oxide (NO) can cause neuronal damage, contributing to the pathogenesis of several neurodegenerative diseases and stroke (i.e., focal cerebral ischemia). NO can mediate neurotoxic effects at least in part via protein S-nitrosylation, a reaction that covalently attaches NO to a cysteine thiol (or thiolate anion) to form an S-nitrosothiol. Recently, the tyrosine phosphatase Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) and its downstream pathways have emerged as important mediators of cell survival. Here we report that in neurons and brain tissue NO can S-nitrosylate SHP-2 at its active site cysteine, forming S-nitrosylated SHP-2 (SNO–SHP-2). We found that NMDA exposure in vitro and transient focal cerebral ischemia in vivo resulted in increased levels of SNO–SHP-2. S-Nitrosylation of SHP-2 inhibited its phosphatase activity, blocking downstream activation of the neuroprotective physiological ERK1/2 pathway, thus increasing susceptibility to NMDA receptor-mediated excitotoxicity. These findings suggest that formation of SNO–SHP-2 represents a key chemical reaction contributing to excitotoxic damage in stroke and potentially other neurological disorders.
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第四届中英癌症生物学前沿研讨会暨CDDIS-中国上海研讨会 2013年5月8-9日 中国上海
