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

Key Points

  • The serine/threonine protein kinase mechanistic target of rapamycin (mTOR) is evolutionarily conserved and modulates protein synthesis, cell growth, and cellular autophagy in response to distinct intracellular and extracellular cues

  • Altered mTOR signalling has been shown to play pathogenic roles in a number of neurological disorders, including epilepsy, autism, intellectual disability, neurodegenerative disorders, CNS tumours, and hypoxic–ischaemic brain injury

  • Causative germline and somatic mutations in a number of genes encoding proteins involved in the mTOR signalling pathway have been identified in malformations of cortical development that cause epilepsy, intellectual disability, and autism

  • Clinical trials with mTOR inhibitors, such as sirolimus and everolimus, have shown that suppression of aberrant mTOR activity is effective in neurodevelopmental disorders, such as tuberous sclerosis complex

  • Future clinical trials of mTOR inhibitors are being considered in neurodegenerative disorders, such as Alzheimer disease and stroke

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.

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Figure 1: The mTOR signalling pathway.
Figure 2: Pathophysiological mechanisms in malformations of cortical development caused by somatic mutations.
Figure 3: Differential roles for mTOR signalling in diverse disease phenotypes.

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Acknowledgements

P.B.C. is supported by the NINDS grant R01NS082343.

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Glossary

mTOR cascade

The integrated cell signalling pathway that receives input from other pathways, such as the PI3K–AKT pathway, as well as from cellular nutrient, amino acid, and energy levels to modulate cell growth, protein translation, ribosome biogenesis, and autophagy.

Ribosomal protein S6 kinase beta-1 (S6K1)

mTOR phosphorylates and thereby activates S6K1 (also known as p70S6K1), an enzyme that phosphorylates several residues of the S6 ribosomal protein, increasing protein synthesis and cell proliferation.

Autophagosomes

Autophagic vesicles or vaculoles required to ensnare and transport cytoplasmic components such as proteins and organelles to lysosomes for degradation.

PTEN

PTEN codes for phosphatase and tensin homologue, a lipid phosphatase and tumour suppressor that inhibits growth and proliferation signals of phosphoinositide 3-kinase (PI3K) by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the plasma membrane.

Malformations of cortical development (MCDs)

Abnormalities in the structural architecture of the brain, in particular the cerebral cortex, that occur during fetal development.

Hemimegalencephaly

A type of malformation of cortical development that is characterized by abnormal structure and increased size of one cerebral hemisphere, usually associated with severe, intractable seizures.

Megalencephaly

A malformation of cortical development characterized by brain enlargement (≥2 standard deviations larger than normal brain size for patient age) and is often associated with intellectual disability, autism, and seizures.

PI3K–AKT–mTOR cascade

The intracellular PI3K–AKT–mTOR signalling pathway is an important regulator of cell growth and cell cycle regulator: in response to stimulation by growth factors, phosphoinositide 3-kinase (PI3K) activation triggers phosphoinositide-dependent kinase 1 (PDK1) to phosphorylate and activate AKT, which then activates mechanistic target of rapamycin (mTOR) via tuberous sclerosis complex and GTP-binding protein Rheb (RHEB) and culminates in phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1, also known as EIF4EBP1).

Cell-autonomous effects

A condition in which only cells containing a mutation exhibit a mutant phenotype.

Megalencephaly–capillary malformation syndrome

A syndromic malformation of cortical development characterized by megalencephaly, polymicrogyria, epilepsy, hydrocephalus, and cutaneous capillary malformations.

PIK3R1

PIK3R1 encodes regulatory p85 subunit of phosphoinositide 3-kinase (PI3K).

PIK3CA

PIK3CA encodes the catalytic p110α subunit of phosphoinositide 3-kinase (PI3K).

Cowden syndrome

Cowden syndrome is characterized by benign tissue overgrowths (hamartomas) affecting the skin, mucous membranes, gastrointectinal tract, and breast tissue — although the hamartomas are benign, people with Cowden syndrome are at increased risk of certain forms of cancer, including breast, thyroid, uterus (endometrial), and kidney cancers; moreover, the syndrome is sometimes associated with megalencephaly.

Bannayan–Riley–Ruvalcaba syndrome (BRRS)

BRRS is a hamartoma syndrome characterized multiple subcutaneous lipomas, macrocephaly and haemangiomas.

Lhermitte–Duclos disease (LDD)

LDD is characterized by the presence of a slowly growing tumour of the cerebellum, known as a dysplastic gangliocytoma; it sometimes occurrs in combination with Cowden syndrome, and can be associated with megalencephaly.

AKT3–FOXG1–reelin pathway

This pathway links the PI3K–AKT signalling pathway to the Forkhead box (FOXG1) family of transcription factors and reelin, a potent secreted chemorepellant that modulates neuronal migration.

GTPase-activating proteins toward Rags 1 (GATOR1)

A protein complex that consists of 3 protein subunits (DEP domain-containing protein 5 (DEPDC5) and nitrogen permease regulator proteins NPRL2 and NPRL3) and inhibits mTOR activity when cellular amino acid levels are low.

Non-cell autonomous effects

A non-autonomous effect occurs when cells containing a mutation cause other cells (regardless of their genotype) to exhibit a mutant phenotype.

Leigh syndrome

Leigh syndrome is a neurological disorder resulting from mutations in either nuclear or mitochondrial DNA; its clinical symptoms include hypotonia, peripheral neuropathy, eye movement abnormalities and blindness.

Eukaryotic translation initiation factor 4E (eIF4E)

eIF4E directs ribosomes to the cap structure in the 5′ region of mRNAs in preparation for translation; when mTOR is activated, phosphorylation of 4E-BP1 by mTOR releases inhibition of eIF4E and facilitates protein translation.

GTP-binding protein Rhes (RHES)

A small GTP-binding protein enriched in the striatum that is homologous to Ras.

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Crino, P. The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol 12, 379–392 (2016). https://doi.org/10.1038/nrneurol.2016.81

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