Role of mTOR in physiology and pathology of the nervous system

Abstract

Mammalian target of rapamycin (mTOR) is a serine–threonine protein kinase that regulates several intracellular processes in response to extracellular signals, nutrient availability, energy status of the cell and stress. mTOR regulates survival, differentiation and development of neurons. Axon growth and navigation, dendritic arborization, as well as synaptogenesis, depend on proper mTOR activity. In adult brain mTOR is crucial for synaptic plasticity, learning and memory formation, and brain control of food uptake. Recent studies reveal that mTOR activity is modified in various pathologic states of the nervous system, including brain tumors, tuberous sclerosis, cortical displasia and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. This review presents current knowledge about the role of mTOR in the physiology and pathology of the nervous system, with special focus on molecular targets acting downstream of mTOR that potentially contribute to neuronal development, plasticity and neuropathology.

Introduction

A serine–threonine protein kinase called mammalian target of rapamycin (mTOR) is mostly known for its role in cell proliferation and growth in non-neural cells. The major role of this kinase is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In terms of molecular mechanism, mTOR is thought to act primarily by phosphorylating eIF-4E binding protein (4E-BP) and p70 ribosomal S6 protein kinase (p70S6K), which are important regulators of protein translation [1]. However, “chemical genomics” performed on yeast identified 400 mutants whose phenotypes (measured as rates of survival) were changed in the presence of rapamycin, a specific inhibitor of mTOR [2], [3]. A large number of genes whose expression is down- or upregulated by mTOR inhibition were also identified by gene expression profiling of Drosophila melanogaster cells treated with rapamycin [4]. Analysis of these rapamycin-dependent mutants suggested that mTOR might be involved in additional cellular functions such as transcription, ubiquitin-dependent proteolysis, autophagy, membrane trafficking, microtubule and actin cytoskeleton dynamics.

Although neurons are post-mitotic (non-proliferative), the size of the neuronal cell soma is also controlled by mTOR [5]. Indeed, one of the characteristic features of diseases accompanied by increased mTOR activity is tissue hypertrophy, which also affects the nervous system, where neuronal cells are enlarged and cell morphology is highly disturbed (see below). However, recent studies revealed a much broader involvement of mTOR in neuronal development, showing that axon guidance, dendrite development, dendritic spine morphogenesis, all require its activity [6], [7], [8], [9]. But a role for mTOR in neuronal physiology extends beyond the developmental period, since mTOR activity is essential for several forms of synaptic plasticity that underlie processes of learning and memory formation [10], [11], [12], [13], [14]. Recently, mTOR was also shown to regulate other brain functions, for example a control of food uptake [15].

Due to the key role that mTOR plays in neuronal physiology, it is not surprising that mTOR signaling is disturbed under various neuropathological conditions. Changed mTOR activity has been reported in brain tumors, tuberous sclerosis, cortical displasia and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease [16], [17], [18], [19], [20], [21], [22].

Yet, in cases of either physiological processes or neuropathology, our knowledge about molecular events downstream of mTOR is rather rudimentary. In this review we discuss current advances in our understanding of mTOR function and dysfunction in the nervous system, at the same time searching for proteins whose expressions are mTOR-dependent and important for normal neuronal physiology.