摘要
神经营养素是重要的神经营养因子,参与多种神经元群的存活、分化和功能。由蛋白水解而成的前体蛋白(神经营养因子的前体)合成是大部分神经营养因子的共同特点,使他们的营养功能呈现出激活形式。然而,这些蛋白的一些神经营养因子前体形式,如神经生长因子的前体 (pro-NGF),已经被显示通过 p75NTR 受体可以诱导其对神经元的相对立作用及触发其凋亡。这也意味着神经营养因子前体与神经营养因子之间的平衡必须严格控制。关于此点,处于像一些神经退行性疾病的老化或发展的氧化应激状态,神经营养因子至少能够被糖基化或脂质氧化终产物(AGE/ALEs)氧化修饰,而生成pro-NGF产物。缺乏成熟和倾向性失衡的先导形式也许会改变活化的细胞凋亡信号通路模式,因此恶化毒化过程,例如在神经退行性疾病发展期。 此外,AGE/ALEs 也可以诱导α分泌酶生成pro-NGF p75NTR受体的进程,其次是被γ分泌酶,且释放胞内区p75NTR (p75NTRICD)。一旦裂开,p75NTRICD会 募集两个胞内相互因子NRIF 和TRAF6, 它允许NPIR被JNK磷酸化。然后NRIF的磷酸化形式转移至细胞核,诱导凋亡蛋白前体表达。本文中,我们将会对哪些ROS诱导蛋白修饰、何种蛋白易受修饰影响、这些修饰是如何影响功能及他们如何与神经退行性疾病相关的机制进行总结。
关键词: 阿尔茨海默病,抗氧化剂,凋亡,神经退变,氧化应激,p75NTR,NGF前体
Current Drug Targets
Title:Oxidative Stress and Neurodegenerative Diseases: A Neurotrophic Approach
Volume: 16 Issue: 1
Author(s): Carme Espinet, Hugo Gonzalo, Catherine Fleitas, Maria Jose Menal and Joaquim Egea
Affiliation:
关键词: 阿尔茨海默病,抗氧化剂,凋亡,神经退变,氧化应激,p75NTR,NGF前体
摘要: Neurotrophins are important neurotrophic factors involved in the survival, differentiation and function of a wide variety of neuron populations. A common feature for most neurotrophins is that they are synthesized as precursor proteins (pro-neurotrophins) that upon being processed by proteolysis render the mature active form responsible for most of their trophic functions. However, some of the pro-neurotrophin form of these proteins, such as the precursor form of NGF (pro-NGF), have been shown to induce opposite effects and trigger apoptosis on neurons through the p75NTR receptor. This suggests that the balance between the levels of proneurotrophin and neurotrophin must be tightly controlled. In this context, it has been shown that in conditions of oxidative stress due for instance to aging or the development of some neurodegenerative disease, neurotrophins are oxidatively modified at least by advanced glycation/lipoxidation end products (AGE/ALEs) which makes pro-NGF refractary to be processed. The lack of maturation and the imbalance in favor of the precursor form may change the pattern of active signaling pathways towards cell death, thus exacerbating the deleterious alterations, for instance during the development of neurodegenerative diseases. Besides that, AGE/ALEs also induce the processing of the pro-NGF receptor p75NTR by α- secretase which is followed by the processing by γ -secretase and the release of the intracellular domain of p75NTR (p75NTRICD). Once cleaved, p75NTRICD recruits two intracellular interactors, NRIF and TRAF6, which allows NRIF phosphorylation by JNK. The phosphorylated form of NRIF then translocates to the nucleus and induces the expression of pro-apoptotic proteins. In this chapter we will summarize the mechanisms by which ROS- induce protein modifications, which proteins are susceptible to be modified, how these modifications affect function and signaling and, finally, how they can be related to neurodegenerative diseases.
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Cite this article as:
Carme Espinet, Hugo Gonzalo, Catherine Fleitas, Maria Jose Menal and Joaquim Egea , Oxidative Stress and Neurodegenerative Diseases: A Neurotrophic Approach, Current Drug Targets 2015; 16 (1) . https://dx.doi.org/10.2174/1389450116666150107153233
DOI https://dx.doi.org/10.2174/1389450116666150107153233 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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