|mTOR, Tau and Neurodegeneration||Papers|
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 diabetes (Gong et al., 2014), cancer (Selvarajah et al., 2015), and neurodegeneration. This paper focuses on neurodegeneration, particularly its association with hyperactive mTOR, over-production of Tau proteins and hyperexcitability. Hyperexcitability could be the origin of neurodegeneration, as it is an early sign of Alzheimer's disease and other neurodegenerative disorders (see Paper 2).
The principal function of mTOR is 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), for the initiation of protein synthesis from mRNA to a globular protein. Since the normal function of a protein requires correct folding, mTOR and its regulatory proteins have the capability to sense a misfolded protein and trigger the synthesis of chaperones (e.g. heat shock proteins HSP70, HSP90, etc.) to ensure accurate folding from the amino acid chain to a three dimensional structure (Qian et al., 2010; Conn and Qian, 2011). However, persistent mTOR activation by the misfolded pathological proteins (e.g. mutated, oxidized or aberrantly phosphorylated) may cause diseases.
mTOR Signaling Pathways
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).
mTOR and Neurodegeneration
Hyperactive mTOR increases the risk for neurodegenerative disorders, such as Alzheimer's disease (Pei and Hugon, 2008; Gouras, 2013), Huntington's disease (Pryor et al., 2014), amyotrophic lateral sclerosis (ALS) (Manuel and Heckman, 2011), and Parkinson's disease (Lan et al., 2016). Below are some of the factors that can lead to hyperactive mTOR.
mTOR and Hyperexcitability
The activation of mTOR has been shown to increase Tau production (Caccamo et al., 2013; Tang et al., 2013; Tang et al., 2015). As discussed in Paper 2, excessive Tau proteins (especially the 4-repeat isoform) may give rise to hyperexcitability. Therefore, hyperactive mTOR should promote hyperexcitability. This novel mechanism is supported by the following observations.
Mounting evidence has suggested that hyperactive mTOR may lead to Tau over-production and neuronal hyperexcitability. This agrees with the MT Model that hyperexcitability arises from the interaction between Tau and microtubules at the axon initial segment (AIS). However, it has been well documented that mTOR plays a key role in synaptic plasticity which can also affect excitability. In this regard, experimental studies found that mTOR hyperactivation is not always associated with enhanced synaptic transmission (Lasarge and Danzer, 2014; Wang et al., 2015). Furthermore, the mTOR-induced hyperexcitability is likely to originate from persistent Na+ current, INaP (Manuel and Heckman, 2011; Carunchio et al., 2010). The major source of INaP is the ionic current through non-inactivating Na+ channel, Nav1.6, which is located predominantly at AIS and nodes of Ranvier (O'Brien and Meisler, 2013).
Author: Frank Lee