Department of Neurology and Neurosciences, Cancer Center, University of Medicine and Dentistry - New Jersey Medical School, Newark, NJ, USA.
Oxid Med Cell Longev. 2010 Nov-Dec;3(6):374-91. doi: 10.4161/oxim.3.6.14787. Epub 2010 Nov 1.
The mammalian target of rapamycin (mTOR) and its associated cell signaling pathways have garnered significant attention for their roles in cell biology and oncology. Interestingly, the explosion of information in this field has linked mTOR to neurological diseases with promising initial studies. mTOR, a 289 kDa serine/threonine protein kinase, plays an important role in cell growth and proliferation and is activated through phosphorylation in response to growth factors, mitogens, and hormones. Growth factors, amino acids, cellular nutrients, and oxygen deficiency can down-regulate mTOR activity. The function of mTOR signaling is mediated primarily through two mTOR complexes: mTORC1 and mTORC2. mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K). In contrast, mTORC2 regulates development of the cytoskeleton and also controls cell survival. Although closely tied to tumorigenesis, mTOR and the downstream signaling pathways are significantly involved in the central nervous system (CNS) with synaptic plasticity, memory retention, neuroendocrine regulation associated with food intake and puberty, and modulation of neuronal repair following injury. The signaling pathways of mTOR also are believed to be a significant component in a number of neurological diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, traumatic brain injury, and ischemic stroke. Here we describe the role of mTOR in the CNS and illustrate the potential for new strategies directed against neurological disorders.
哺乳动物雷帕霉素靶蛋白（mTOR）及其相关细胞信号通路因其在细胞生物学和肿瘤学中的作用而受到广泛关注。有趣的是，该领域信息的爆炸式增长将 mTOR 与神经退行性疾病联系起来，初步研究显示出可喜的前景。mTOR 是一种 289kDa 的丝氨酸/苏氨酸蛋白激酶，在细胞生长和增殖中发挥重要作用，并通过对生长因子、有丝分裂原和激素的磷酸化而被激活。生长因子、氨基酸、细胞营养物质和缺氧可下调 mTOR 活性。mTOR 信号的功能主要通过两种 mTOR 复合物：mTORC1 和 mTORC2 来介导。mTORC1 通过磷酸化真核起始因子 4E 结合蛋白 1（4EBP1）和 p70 核糖体 S6 激酶（p70S6K）启动帽依赖性蛋白翻译，这是蛋白质合成的限速步骤。相比之下，mTORC2 调节细胞骨架的发育，还控制细胞存活。尽管与肿瘤发生密切相关，但 mTOR 和下游信号通路在中枢神经系统（CNS）中也具有重要作用，包括突触可塑性、记忆保留、与进食和青春期相关的神经内分泌调节，以及损伤后神经元修复的调节。mTOR 的信号通路也被认为是许多神经退行性疾病（如阿尔茨海默病、帕金森病、亨廷顿病、结节性硬化症、神经纤维瘤病、脆性 X 综合征、癫痫、创伤性脑损伤和缺血性中风）的一个重要组成部分。本文描述了 mTOR 在 CNS 中的作用，并说明了针对神经退行性疾病的新策略的潜力。
