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.

Figure 1. Domain structure of the mTOR kinase and components of its protein complexes

A. Domain organization of the mTOR kinase. HEAT (huntingtin, elongation factor 3, a subunit of phosphatase 2A and TOR1) repeats mediate protein interactions with Raptor, Rictor, and other proteins; FKBP12-rapamycin binding domain (FRB) is the site of rapamycin-mediated inhibition of mTORC1; The PIKK kinase domain contains the Ser/Thr catalytic activity and is the site of inhibition of kinase-site inhibitors such as Torin1 and Torin II, which inhibit both mTORC1 and mTORC2 activity; FATC = FRAP-ATM-TTRAP domain. B. The components of mTORC1 and mTORC2. mTOR = mechanistic target of rapamycin; Raptor= scaffolding protein essential to mTORC1 activity and rapamycin sensitivity; PRAS40 = an inhibitor of mTORC1; DEPTOR = an inhibitor of mTORC1; mLST8/GβL = function unclear; Rictor = scaffold protein essential to mTORC2 function; mSIN1 = important for mTORC2 enzymatic activity toward AKT; Protor = mediates activity toward SGK. Black outlines indicate proteins that have been thoroughly examined in the nervous system. The dashed line around FKBP12 indicates that it is a non-obligate component of mTORC1.

Figure 2. The mTOR Signaling Pathway

The mTOR complexes integrate signals from nutrients, growth factors, cytokines, and various intracellular influences to elicit a variety of crucial cellular responses. While there are thousands of mTOR substrates, those that have been best characterized in the regulation of crucial cellular processes such as protein synthesis and autophagy are depicted. Abbreviations not found in text include: RTKs = receptor tyrosine kinases; TrkB = tyrosine receptor kinase B, the receptor for BDNF (brain-derived neurotrophic factor); mGluRs = metabotropic glutamate receptors; NMDA-R = N-methyl-D-aspartate receptor; PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha).

Figure 3. The mTOR Pathway in Neurodevelopmental and Neurodegenerative Diseases

The small inset at the top depicts the physiological regulation of mTOR signaling by a variety of intrinsic and extrinsic factors. Downstream of mTOR, several cellular processes are regulated, including protein synthesis, mitochondrial biogenesis and autophagy. A. Neurodevelopmental disease: The larger box depicts how loss of NF-1, TSC1/2, or PTEN, or environmental stimuli such as inflammation, epilepsy, or hypoxia may stimulate mTOR-dependent protein synthesis result in in a host of cellular, structural and physiological responses that culminate in clinical symptoms. B. Neurodegenerative disease: The larger box models how changes in these factors may result in dysregulation of mTOR-dependent cellular processes, most notably autophagy, mitochondrial function and protein synthesis. Dysfunctional autophagy has been widely associated with neurodegenerative disease.