Molecular neurobiology of mTOR

Abstract

Mammalian/mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that controls several important aspects of mammalian cell function. mTOR activity is modulated by various intra- and extracellular factors; in turn, mTOR changes rates of translation, transcription, protein degradation, cell signaling, metabolism, and cytoskeleton dynamics. mTOR has been repeatedly shown to participate in neuronal development and the proper functioning of mature neurons. Changes in mTOR activity are often observed in nervous system diseases, including genetic diseases (e.g., tuberous sclerosis complex, Pten-related syndromes, neurofibromatosis, and Fragile X syndrome), epilepsy, brain tumors, and neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease). Neuroscientists only recently began deciphering the molecular processes that are downstream of mTOR that participate in proper function of the nervous system. As a result, we are gaining knowledge about the ways in which aberrant changes in mTOR activity lead to various nervous system diseases. In this review, we provide a comprehensive view of mTOR in the nervous system, with a special focus on the neuronal functions of mTOR (e.g., control of translation, transcription, and autophagy) that likely underlie the contribution of mTOR to nervous system diseases.

Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys

“…The finding that upregulation of the mTOR signaling pathways correlated with persistent viral loads in both CSF and LN suggests that ZIKV infection may directly stimulate mTOR machinery, which promotes survival of infected cells. Moreover, mTOR signaling has been shown to play a key role in neurodevelopment, including the proliferation of neural stem cells, neuronal circuit development, plasticity, and higher complex functions (Lipton and Sahin, 2014; Switon et al, 2017; Thoreen, 2017). Overexpression of mTOR during early embryonic development in transgenic mice resulted in cortical atrophy and microcephaly, whereas overexpression of mTOR in adults led to neurodegeneration (Kassai et al, 2014).…”

Methylmercury Induced Neurotoxicity and the Influence of Selenium in the Brains of Adult Zebrafish (Danio rerio)

“…RICTOR defines a distinct mammalian mTOR pathway which regulates protein kinase C alpha (PKCα) and protein kinase B (Akt/PKB) signalling networks [28]. Within the mTOR pathway, the interplay between two protein complexes, mTORC1 and the RICTOR containing mTORC2, play an essential role in neural development [29]. While the mTOR pathway is complex and not completely understood, suppression and/or overactivation of either mTORC1 or mTORC2 results in dysregulation of neuronal morphology and function [30].…”

Plasticity of Spine Structure: Local Signaling, Translation and Cytoskeletal Reorganization

“…Finally, the mTOR complex 2 (mTORC2) pathway, a major pathway that regulates protein synthesis, is also found to regulate dynamics of actin cytoskeleton through Rac1 activation (Huang et al, 2013; Switon et al, 2017). Although the precise mechanism of mTORC2-mediated remodeling of actin cytoskeleton remains elusive, it has been proposed that the recruitment of Tiam1, a Rac1-specific guanine exchange factor (GEF), by Rictor, an essential component of mTORC2, regulates Rac1 activity and subsequent actin polymerization (Huang et al, 2013).…”