Cellular and Molecular Signaling, Newark, NJ, USA.
Neural Regen Res. 2014 Aug 1;9(15):1413-7. doi: 10.4103/1673-5374.139453.
Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer's disease, and Parkinson's disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin (mTOR). mTOR is a component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence. mTOR through its relationship with phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) and multiple downstream signaling pathways such as p70 ribosomal S6 kinase (p70S6K) and proline rich Akt substrate 40 kDa (PRAS40) promotes neuronal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and β-amyloid toxicity may offer new strategies for disorders such as stroke and Alzheimer's disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clinical efficacy and eliminate any clinical toxic side effects.
神经退行性疾病影响着全球超过 3000 万人，导致严重残疾和死亡。随着全球人口寿命和年龄的增长，以及个体更容易受到急性疾病（如中风）和涉及认知丧失的慢性疾病（如阿尔茨海默病和帕金森病）的影响，这些统计数据将呈指数级增长。目前针对这些疾病的治疗方法仅对一小部分患者有效，或者只能提供症状缓解，但不能改变疾病的进展。一种令人兴奋的治疗方法可能会改变神经退行性疾病的治疗局面，那就是哺乳动物雷帕霉素靶蛋白（mTOR）。mTOR 是蛋白复合物 mTOR 复合物 1（mTORC1）和 mTOR 复合物 2（mTORC2）的组成部分，它们在全身广泛存在，控制着多种功能，如基因转录、代谢、细胞存活和细胞衰老。mTOR 通过与磷酸肌醇 3-激酶（PI 3-K）和蛋白激酶 B（Akt）以及多个下游信号通路（如 p70 核糖体 S6 激酶（p70S6K）和富含脯氨酸的 Akt 底物 40kDa（PRAS40））的关系，促进神经元细胞再生，通过干细胞更新，并监督细胞凋亡、自噬和坏死等关键途径，以保护免受神经退行性疾病的侵害。mTOR 对驱动长时程增强、突触可塑性和β-淀粉样毒性的特定途径的靶向作用可能为中风和阿尔茨海默病等疾病提供新的治疗策略。总的来说，mTOR 是一种重要的神经保护途径，但必须谨慎靶向，以最大限度地提高临床疗效，并消除任何临床毒性副作用。
