J Korean Neurosurg Soc.  2019 May;62(3):272-287. 10.3340/jkns.2019.0027.

Mechanistic Target of Rapamycin Pathway in Epileptic Disorders

• Kim JK
• Lee JH

• KMID: 2453232
• DOI: http://doi.org/10.3340/jkns.2019.0027

Abstract

The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.

Keyword

mTORC1; mTORC2; Epilepsy; Malformation of cortical development

MeSH Terms

Biological Processes
Brain
Drug Resistant Epilepsy
Epilepsies, Partial
Epilepsy
Eukaryotic Cells
Humans
Intercellular Signaling Peptides and Proteins
Malformations of Cortical Development
Nervous System
Oxygen
Sirolimus*
Intercellular Signaling Peptides and Proteins
Oxygen
Sirolimus

Figure

• 

  Fig. 1. mTORC1 and mTORC2. A : The components of mTORC1 and respective binding site on mTOR. B : The components of mTORC2 and respective binding site on mTOR. PRAS40 : proline-rich Akt substrate of 40 kDa, Raptor : regulatory protein associated with mTOR, FKBP12 : FK506 binding protein 12, Deptor : DEP domain-containing mTORinteracting protein, mLST8 : mammalian lethal with Sec13 protein 8, mTOR : mechanistic target of rapamycin, mTORC1 : mTOR complex 1, mSin1 : mammalian stress-activated protein kinase-interacting protein, Rictor : rapamycin-insensitive companion of mammalian target of rapamycin, mTORC2 : mTOR complex 2.

• 

  Fig. 2. Upstream and downstream of mTORC1 and mTORC2. The signaling network of mTORC1 and mTORC2. Positive regulators of mTORC1 signaling are shown in blue to green. Negative regulators of mTORC1 signaling are shown in red to yellow.

Reference

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