Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewRole of mTOR in physiology and pathology of the nervous system
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.
Section snippets
mTOR—an important convergence point in cell signaling
mTOR kinase activity is modulated in response to various stimuli such as trophic factors, mitogens, hormones, amino acids, cell energy status and cellular stress, including ischemia, heat shock, DNA damage and viral infections [23], [24], [25], [26], [27]. These positive and negative signals converge on mTOR, the resultant activity of which sets the balance between anabolic and catabolic processes in the cell. mTOR kinase activity regulates numerous cellular processes both in positive (for
mTOR kinase activity in physiology of the nervous system
Availability of selective inhibitors of mTOR, methodological advances in genetic modification of neuronal cells, and an increase in interest in mTOR functions have greatly accelerated our understanding role of mTOR in the physiology of the nervous system. Although research has primarily focused on the mTOR-dependent translation impact on synaptic and brain plasticity [10], [13], [89], several recent studies addressed questions about mTOR involvement in neuronal development [90] and aspects of
mTOR-related pathologies of the nervous system
Deregulation of mTOR signaling has been implicated in several diseases, especially different types of cancer, including brain tumors, particularly those involving mutations in genes encoding upstream regulators of mTOR activity, such as PI3K, Akt or PTEN. Since several reviews have appeared in this area [18], [121], [122], [123], [124], we rather focus here on still underinvestigated correlations between disturbances in mTOR activity in multiorgan diseases affecting also the brain, and
Perspectives for application of the mTOR inhibitors in the nervous system—promises and caveats
Rapamycin and its analogues (AP-23573; RAD001; CCI-779) could be potential therapeutics in multiple human diseases (Table 2). Rapamycin has been used as an anti-rejection drug for kidney transplants for the last 10 years and is approved for treatment in cardiovascular diseases (drug-coated stents) [147], [148]. Another mTOR inhibitor, temsirolimus, has just been approved for treatment of renal cell carcinoma [149], [150], [151]. mTOR inhibitors could be used to treat other diseases, including
Conclusion and perspective
Our understanding of the role of mTOR in physiology of developing and differentiated neuronal cells is presently dramatically increasing. Considerable progress is also being reported on the changes in mTOR activity accompanying brain disease. However, we are still far from understanding how modifications in mTOR activity contribute to disease progress. An important aspect still missing, and urgently required, is identification of downstream mTOR effectors in the nervous system. This would lead
Acknowledgments
We thank Prof. David Shugar for the invitation to present this topic at the IPK2007 conference in Warsaw. The authors appreciate comments on the manuscript by Prof. Shugar, Prof. Kaczmarek and Dr. Bochtler. This work was supported by the Polish Ministry of Science and Higher Education grant no. PBZ-MNiI-2/1/2005 to J.J.
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These authors equally contributed to this work.