mTOR signaling and its roles in normal and abnormal brain development

Abstract

Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mammalian TOR (mTOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.

Keywords: BDNF; CNS neurons; TSC/mTOR; amino acids; brain malformation; mTORC1 signaling; protein synthesis; translational control.

FIGURE 1

Upper panel. Domain structure of mTOR. HEAT: Huntington Elongation Factor 3 PR65/A TOR, FAT: FRAP ATM TTRAP, FRB: FKBP12-Rapamycin Binding. Middle and lower panel: Components of mTOR complexs.

FIGURE 2

The flow sheet of upstream and downstream of mTORCs. Representative substrates and cellular responses mentioned in the text are shown. Note that mTORC2 activates mTORC1 through Akt.

FIGURE 3

Scheme of translation processes that are regulated by mTORC1. Upper panel: translation initiation. mTORC1 directly phosphorylates 4EBP and liberates eIF4E. eIF4E with mRNA then binds to eIF4G to form eIF4F complex. Phosphorylation of eIF4G and eIF4B is mTORC1-dependent. Assembly of eIF3 subunits and eIF4G is also thought to be mTORC1-dependent. Lower panel: translation elongation. p70S6K downstream of mTORC1 phosphorylates eEF2K and suppresses its activity to phosphorylate eEF2. Non-phosphorylated form of eEF2 is an active form thus enhances elongation process.

FIGURE 4

A graphic of hypothetical neuronal development governed by mTORC1. Neurons receive nutrients globally and growth factors/transmitters locally. Both inputs coordinately activate mTORC1 that leads normal neuronal development. Suppression or overactivation of mTORC1 result dysregulation of neuronal morphology and function. (note that photographs of a neuron was image processed).