Geon Epilepsy and mTOR Topics

 

mTOR refers to "mechanistic (or mammalian) target of rapamycin". It has been demonstrated to play pivotal roles in a wide range of human diseases, including neurodegeneration, diabetes, cardiac hypertrophy, and cancer (see mTOR: The Ultimate Risk Factor). The principal function of mTOR is the stimulation of protein synthesis, in response to a variety of signals: glucose, amino acids, insulin, growth factors, cytokines, protein misfolding, etc. mTOR is a protein kinase that catalyzes protein phosphorylation. Upon activation, it can phosphorylate two major targets, p70 ribosome S6 kinase1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), which are required for protein synthesis from mRNA to a globular protein. The activation of mTOR has been shown to increase Tau production (Caccamo et al., 2013; Tang et al., 2013; Tang et al., 2015). On the other hand, over-production of Tau proteins has been demonstrated to cause hyperexcitability or seizures (Holth et al., 2013; DeVos et al., 2013; Li et al., 2014). Therefore, hyperactive mTOR is a risk factor for epilepsy.

mTOR Signaling Pathways

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Figure 1. Schematic diagram of major pathways leading to the activation of mTORC1. Protein misfolding may activate mTORC1 via Raptor (not shown). [Source: Melnik et al., 2012]

In mammalian cells, mTOR exists in two functionally and structurally distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 consists of mTOR, Raptor, PRAS40, and mLST8 while mTORC2 comprises mTOR, Rictor, mSIN1, and mLST8. Rapamycin can inhibit mTORC1, but its effect on mTORC2 is more complex. Tau proteins are produced from the activation of mTORC1.

Figure 1 shows the major pathways leading to the activation of mTORC1. The misfolded proteins can also activate mTORC1, possibly via Raptor (Qian et al., 2010). Generally, the activation of mTORC1 requires two parallel processes: (1) activation of Rheb (Ras homolog enriched in brain) which is a GTP-binding protein, and (2) translocation of inactive mTORC1 to late endosome or lysosome where active Rheb is located (Melnik et al., 2012). The second process can be induced by amino acids, in particular, leucine. Rheb is negatively regulated by tuberous sclerosis complex (TSC1 or TSC2) which, in turn, is subject to regulation of Akt (protein kinase B) and AMPK (AMP-activated protein kinase).

Hyperactive mTOR may Cause Epilepsy

As described above, hyperactive mTOR may cause seizures by increasing Tau production. This novel mechanism is supported by the following observations.

 

Author: Frank Lee
First published: December 9, 2015
Last updated: April 1, 2017