哺乳动物雷帕霉素靶蛋白在脑生理和病理中的作用

Role of mammalian target of rapamycin in brain physiology and pathology

哺乳动物雷帕霉素靶蛋白(mTOR)常被用于研究免疫抑制剂药物雷帕霉素的功能和作用机制。作为丝氨酸/苏氨酸激酶,mTOR有两种功能明显不同的复合体——mTORC1和mTORC2,控制诸如蛋白质合成,能量代谢,细胞大小,脂质代谢,自噬,线粒体功能和溶酶体形成等细胞的基本功能。此外,mTOR控制的信号通路还参与调节神经系统的许多生理功能,包括神经系统的发育,突触可塑性,记忆储存和认知功能。因此,mTOR信号通路失调可能与许多神经和精神疾病的发生有关。前期研究表明,抑制mTORC1对癫痫、认知障碍和脑部肿瘤等疾病的治疗有利,而直接或间接刺激mTORC1一方面可促进脑细胞轴突再生和骨髓鞘形成,另一方面该通路可成为治疗抑郁症的靶点之一。

Target of rapamycin（ TOR） and its mammalian ortholog mammalian target of rapamycin（ mTOR） have been discovered in an effort to understand the mechanisms of action of the immunosuppressant drug rapamycin. mTOR is a serine/threonine kinase existed in two functionally distinct complexes,mTORC1 and mTORC2,which control many basic cellular functions such as protein synthesis,energy metabolism,cell size,lipid metabolism,autophagy,mitochondria and lysosome biogenesis. In addition,mTOR-controlled signaling pathways regulate many integrated physiological functions of the nervous system including neuronal development,synaptic plasticity,memory storage,and cognition. Thus it is not surprising that deregulation of mTOR signaling may involve in many neurological and psychiatric disorders. Preclinical and preliminary clinical studies indicate that inhibition of mTORC1 can be beneficial for some pathological conditions such as epilepsy,cognitive impairment,and brain tumors,while a direct or indirect stimulation of mTORC1 can be beneficial for other pathologies such as depression or axonal growth and regeneration.