Review
mTOR: on target for novel therapeutic strategies in the nervous system

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The mammalian target of rapamycin (mTOR), the key component of the protein complexes mTORC1 and mTORC2, plays a critical role in cellular development, tissue regeneration, and repair. mTOR signaling can govern not only stem cell development and quiescence but also cell death during apoptosis or autophagy. Recent studies highlight the importance of both traditional and newly recognized interactors of mTOR, such as p70S6K, 4EBP1, GSK-3β, REDD1/RTP801, TSC1/TSC2, growth factors, wingless, and forkhead transcription factors, that influence Alzheimer's disease, Parkinson's disease, Huntington's disease, tuberous sclerosis, and epilepsy. Targeting mTOR in the nervous system can offer exciting new avenues of drug discovery, but crucial to this premise is elucidating the complexity of mTOR signaling for robust and safe clinical outcomes.

Section snippets

The mammalian target of rapamycin (mTOR)

The mammalian target of rapamycin (mTOR), also termed the mechanistic target of rapamycin and FK506-binding protein 12-rapamycin complex-associated protein 1 (FRAP1), is a 289 kDa protein serine/threonine protein kinase that plays a critical role in protein synthesis, cytoskeletal organization, cellular differentiation, development, survival, and aging [1] (Box 1). In mammals, a single gene FRAP1 encodes mTOR and mTOR is ubiquitously expressed as a protein throughout the body including the

Phosphorylation domains of mTOR

The carboxy-terminal domain of mTOR consists of a conserved sequence with homology to the catalytic domain of phosphoinositide 3-kinase (PI 3-K) (the catalytic PI 3/PI 4-related kinase domain) as well as other domains that include FKBP12 (FK506-binding protein 12)–rapamycin-binding domain (FRB) that is the docking site for the FKBP12–rapamycin complex, FAT domain [FKBP-associated protein (FRAP), ataxia telengiectasia (ATM), transactivation/transformation domain-associated protein (TRRAP)], and

Complexes, targets, and regulation of mTOR

The distinct signaling pathways of mTOR rely upon the formation of two protein complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) 1, 6 (Figure 1). mTORC1 relies upon the Raptor protein to allow mTORC1 to bind to its complex constituents (Table 2), and phosphorylation of Raptor, and consequent regulation of mTORC1 activity, can occur through multiple pathways. One Raptor phosphorylation pathway involves the protein Ras homolog enriched in brain (Rheb). Rheb can increase

Role of mTOR in stem cell development, proliferation, and quiescence

mTOR can have a significant impact upon stem cell development, proliferation, and quiescence (Table 3). For example, deletion of the C-terminal six amino acids of mTOR, which are essential for kinase activity, decreases in proliferation of embryonic stem cells [31]. Complete ablation of mTOR leads to lethality and the arrest of embryonic stem cell proliferation [32].

The activity of mTOR is essential for the long-term undifferentiated growth of human embryonic stem cells, as demonstrated by the

Oxidative stress pathways of mTOR during apoptosis and autophagy

Although diseases that affect various systems of the body may have multiple etiologies, oxidative stress can be a primary component that leads to the onset and progression of both acute and chronic disorders in the nervous system. Disorders associated with aging, cognitive loss, immune system impairment, or metabolic disorders may be the result of the release of reactive oxygen species (ROS) that lead to oxidative stress [47] and recent studies link ROS to DNA damage in diabetic patients [48],

Alzheimer's disease

mTOR may be necessary for synaptic plasticity and memory formation in the hippocampus, given that mTOR inhibition has been shown to impair memory consolidation [79] (Table 3). Yet as the data below illustrates, the degree of activity in mTOR pathways needed to be therapeutic in disorders such as AD has not been determined. An increase in phosphorylated levels of substrates, such as mTOR, GSK-3β, and tau protein, has been observed in AD, indicating that these substrates may promote AD

Concluding remarks and future perspectives

mTOR and its signaling pathways have a significant impact on multiple disorders of the nervous system, including AD, PD, HD, TS, and epilepsy. Therefore, targeting mTOR for the development of novel therapeutic avenues to treat neurodegenerative disorders is viewed with great enthusiasm. Both newly recognized pathways of growth factors, wingless, and forkhead transcription factors and traditional known pathways of mTORC1 and mTORC2 that involve p70S6K, 4EBP1, PI 3-K, Akt, AMPK, GSK-3β, REDD1,

Disclaimer statement

There are no conflicts to disclose.

Acknowledgments

We apologize to our colleagues whose work we were unable to cite as a result of article space limitations. This research was supported by the following grants to K.M.: American Diabetes Association, American Heart Association (National), Bugher Foundation Award, LEARN Foundation Award, National Institutes of Health, National Institute of Environmental Health Sciences, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and American Recovery and Reinvestment Act.

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