Mammalian Target of Rapamycin: Hitting the Bull′s‐Eye for Neurological Disorders

Abstract

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 downregulate 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 disease, Parkinson disease and Huntington 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.

Effects of <i>Salidroside</i> on Cobalt Chloride-Induced Hypoxia Damage and mTOR Signaling Repression in PC12 Cells

“…40) In addition, inhibition of mTOR activity by rapamycin decreases cell survival and increases apoptotic injury in neurons and microglia during OGD. [41][42][43] Erythropoietin, the hematopoietic growth factor and neuronprotectant, has been shown to protect microglia against OGD through enhancing mTOR activity and preventing mitochondrial cytochrome c release, since inhibition of mTOR by using rapamycin abrogates the cytoprotection of erythropoietin. 44) Rapamycin can also increase the brain infarct size as well as increase the neurological deficit scores following focal cerebral ischemia in rats.…”

The functions of mTOR in ischemic diseases

“…It is possible that the signaling pathways of mTOR may provide protection against apoptosis. In particular, a number of neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and other diseases, such as tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, autophagy, traumatic brain injury, and ischemic stroke, may gain substantial benefits by either activating or inhibiting mTOR activity (49). Glial cell linederived neurotrophic factor and hepatocyte growth factor are strongly associated with not only the anti-apoptotic but also the anti-autophagic effects of mTOR signaling pathways (50).…”

Deconvoluting mTOR biology

“…[1][2][3][4][5] relevant to nervous system biology. As a regulator of protein translation in nerve cells (neurons), mTOR signaling controls synaptic plasticity by modulating longterm potentiation (LTP) and long-term depression (LTD), important for memory and learning.…”