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通过哺乳动物雷帕霉素靶蛋白揭示神经退行性疾病的新曙光。

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin.

机构信息

Laboratory of Cellular and Molecular Signaling, Cancer Center, F 1220, New Jersey Health Sciences University, 205 South Orange Avenue, Newark, NJ 07101, USA.

出版信息

Prog Neurobiol. 2012 Nov;99(2):128-48. doi: 10.1016/j.pneurobio.2012.08.001. Epub 2012 Aug 15.

Abstract

Neurodegenerative disorders affect a significant portion of the world's population leading to either disability or death for almost 30 million individuals worldwide. One novel therapeutic target that may offer promise for multiple disease entities that involve Alzheimer's disease, Parkinson's disease, epilepsy, trauma, stroke, and tumors of the nervous system is the mammalian target of rapamycin (mTOR). mTOR signaling is dependent upon the mTORC1 and mTORC2 complexes that are composed of mTOR and several regulatory proteins including the tuberous sclerosis complex (TSC1, hamartin/TSC2, tuberin). Through a number of integrated cell signaling pathways that involve those of mTORC1 and mTORC2 as well as more novel signaling tied to cytokines, Wnt, and forkhead, mTOR can foster stem cellular proliferation, tissue repair and longevity, and synaptic growth by modulating mechanisms that foster both apoptosis and autophagy. Yet, mTOR through its proliferative capacity may sometimes be detrimental to central nervous system recovery and even promote tumorigenesis. Further knowledge of mTOR and the critical pathways governed by this serine/threonine protein kinase can bring new light for neurodegeneration and other related diseases that currently require new and robust treatments.

摘要

神经退行性疾病影响了世界上相当一部分人口,导致全球近 3000 万人残疾或死亡。哺乳动物雷帕霉素靶蛋白(mTOR)是一种新型治疗靶点,可能对涉及阿尔茨海默病、帕金森病、癫痫、创伤、中风和神经系统肿瘤的多种疾病实体具有治疗潜力。mTOR 信号通路依赖于 mTORC1 和 mTORC2 复合物,该复合物由 mTOR 和几种调节蛋白组成,包括结节性硬化复合物(TSC1、错构瘤/TSC2、结节性硬化症)。通过涉及 mTORC1 和 mTORC2 的许多整合细胞信号通路以及与细胞因子、Wnt 和叉头相关的更新型信号通路,mTOR 可以通过调节促进凋亡和自噬的机制,促进干细胞增殖、组织修复和长寿以及突触生长。然而,mTOR 通过其增殖能力有时可能对中枢神经系统的恢复有害,甚至促进肿瘤发生。进一步了解 mTOR 及其丝氨酸/苏氨酸蛋白激酶调控的关键途径,可以为神经退行性疾病和其他目前需要新的和强大治疗方法的相关疾病带来新的启示。

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