The mTOR signalling cascade: paving new roads to cure neurological disease

Abstract

Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

“…The PI3K-Akt-mTOR pathway is critical for neurite outgrowth, synaptic plasticity, and learning and memory (Crino, 2016). To evaluate whether miR-137 regulates mTOR activity, we transfected primary cortical neurons with a plasmid to overexpress the miR-137 precursor (pre-miR-137 OE or miR-137 OE) and detected changes in mTOR by western blot.…”

Multimodal MRI profiling of focal cortical dysplasia type II

“…Such approaches may also benefit minimally invasive thermal ablation, which does not supply tissue specimen for analysis. 39 Notably, however, future studies are needed to assess generalizability and scalability of our algorithms across sites and imaging platforms. Moreover, subtype-specific multiparametric models of FCD are likely to increase the sensitivity of automatic lesion classification methods, particularly for detection of subtle dysplasias.…”

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

“…mTOR is a large molecule, encoded by the MTOR gene (1p36), and its structure consists of HEAT repeats (interaction domain with regulatory-associated protein of mTOR or rapamycin-insensitive companion of mTOR), FRAP-ATM-TTRAP (FAT; proteineprotein interaction domain), FRB (rapamycin binding domain), kinase domain (interaction with mammalian lethal with SEC13 protein 8), and catalytic active domain in C-terminus and interaction sites of regulatory-associated protein of mTOR, rapamycin-insensitive companion of mTOR, and mammalian lethal with SEC13 protein 8. 3 By input from upstream regulatory proteins of growth factors, ATP, and so on, MTOR makes phosphorylation of downstream proteins to cell growth, conservancy, and survival. MTOR also leads to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1 (4EBP1), direct regulators of translation initiation, and results to induce translation pathway and increase in cell size, as well as migratory and invasive behavior of cells.…”