The Neurology of mTOR

Abstract

The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.

A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

“…4,5 Moreover, mutations in other components of mTOR could manifest neurological symptoms without megalencephaly, such as ID, autism or epilepsy, as seen in patients with mutations in TSC1 (tuberous sclerosis complex 2), TSC2, PINK1 and DISC1. 6 These findings strongly support the role of the mTOR pathway in the development and function of the brain. In this study, we provide evidence linking mutation in HERC1, another regulator of the mTOR pathway, to a distinct form of megalencephaly.…”

mTORC1 signaling activates NRF1 to increase cellular proteasome levels

“…42,57,58 In model organisms from yeast to mice, the mTORC1 inhibitor rapamycin has been shown to promote longevity, leading to intense interest in the use of mTORC1 inhibitors for specific aging-related diseases, especially those with underlying defects in proteostasis, such as neurodegenerative diseases. 58,59 For instance, mTORC1 signaling is elevated in the brains of patients with Alzheimer disease (AD), and rapamycin is effective in AD mouse models, where it is believed that the resulting induction of autophagy facilitates the clearance of protein aggregates. 60,61 A question that arises from our recent findings 12 is whether the reciprocal control of autophagy and proteasome levels by mTORC1 is fully maintained as cells, tissues, and organisms age.…”

“…62 mTORC1 also plays a key role in neurocognition and behavior, including autism, which is thought to be through effects on synaptic plasticity, 59 a process that requires dynamic control of protein synthesis and degradation. Importantly, we found that mTORC1 activation in cortical neurons leads to the accumulation of NRF1 and expression of PSM genes, suggesting that mTORC1 regulates the proteasome content of neurons, which could influence its role in both neurodegeneration and synaptic plasticity.…”

The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimer's disease

“…Just like the PI3K/AKT/ GSK-3β pathway, activated AKT activates mTOR. Activated mTOR works as an atypical serine/threonine protein kinase regulating cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription [52]. mTOR is present in two distinct complexes: mTOR complex 1(mTORC1) including mTOR, Raptor, GβL, and DEPTOR and mTORC2 with mTOR, Rictor, GβL, Sin1, PRR5/Protor-1, and DEPTOR.…”