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Review
. 2013 Mar-Apr;36(2):40-50.
doi: 10.4103/2319-4170.110365.

Mammalian target of rapamycin (mTOR) pathways in neurological diseases

Michael Wong  1
Affiliations
Review

Mammalian target of rapamycin (mTOR) pathways in neurological diseases

Michael Wong. Biomed J. 2013 Mar-Apr.

Abstract

The mammalian target of rapamycin (mTOR) pathway is an essential cellular signaling pathway involved in a number of important physiological functions, including cell growth, proliferation, metabolism, protein synthesis, and autophagy. Dysregulation of the mTOR pathway has been implicated in the pathophysiology of a number of neurological diseases. Hyperactivation of the mTOR pathway, leading to increased cell growth and proliferation, has been most convincingly shown to stimulate tumor growth in the brain and other organs in the genetic disorder, tuberous sclerosis complex (TSC). In addition, mTOR may also play a role in promoting epileptogenesis or maintaining seizures in TSC, as well as in acquired epilepsies following brain injury. Finally, the mTOR pathway may also be involved in the pathogenesis of cognitive dysfunction and other neurological deficits in developmental disorders and neurodegenerative diseases. mTOR inhibitors, such as rapamycin and its analogs, may represent novel, rational therapies for a variety of neurological disorders.

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Figures

Fig. 1
Fig. 1
Physiological regulation of the mTOR pathway. The mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase, which forms two complexes, rapamycin-sensitive mTORC1,and relatively rapamycin-insensitive mTORC2 (not shown). mTORC1 activates downstream signaling mechanisms involved in ribosomal biogenesis (S6K, Ribosomal S6) and protein translation (4E-BP1, eIF4E). Through regulation of protein synthesis and other mechanisms, the mTOR pathway modulates a number of important physiological processes, such as cell growth and proliferation, metabolism, and brain-specific functions (e.g., synaptic reorganization, ion channel expression, neuronal death). In turn, the mTOR pathway may be activated or inhibited by various physiological stimuli via various upstream signaling pathways and intermediary proteins (TSC1, TSC2, Rheb). AMPK - 5′ adenosine monophosphate-activated protein kinase; eIF4E, elongation initiation factor 4E; mTOR - mammalian target of rapamycin; PI3K - phosphoinositide-3 kinase; PTEN, phosphatase and tensin homolog on chromosome 10; Rheb - Ras homolog enriched in brain; STRADα – STE20-related kinase adapter alpha; S6 - ribosomal protein S6; S6K - ribosomal S6 kinase; TSC1 - tuberous sclerosis complex 1 protein; TSC2 - tuberous sclerosis complex 2 protein; 4E-BP1 - elongation factor 4E binding protein 1.
Fig. 2
Fig. 2
Pathological regulation of the mTOR pathway in neurological disease. Dysregulation of the mTOR pathway has been implicated in the pathophysiology of a variety of different neurological diseases. In some disorders (shown in black boxes), there is convincing evidence of a direct molecular or genetic link between the disease and a specific upstream component of the mTOR pathway, specifically TSC and hamartin/tuberin, polyhydramnios, megalencephaly and symptomatic epilepsy syndrome (PMSE) and STRADα, and glioblastoma and PTEN. In other disorders (shown in gray boxes), the mechanistic link to the mTOR pathway is not as well established, although there is some evidence that traumatic brain injury (TBI), other acquired epilepsies, and fragile X syndrome may involve activation of PI3K/Akt. The least is known about how neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease, affect the mTOR pathway, although downstream effects likely involve regulation of autophagy, clearance of protein aggregates, and neuronal death mechanisms. See legend to Fig. 1 for other abbreviations.
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