Journal ArticleDOI
The mTOR signalling cascade: paving new roads to cure neurological disease
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TLDR
To understand how altered mTOR signalling leads to such divergent phenotypes, insight is needed into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling.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.read more
Citations
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Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis
TL;DR: The roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways are discussed, and gaps in knowledge are identified and perspective directions for research are delineated.
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MicroRNAs in epilepsy: pathophysiology and clinical utility
David C. Henshall,Hajo M. Hamer,R. Jeroen Pasterkamp,David Goldstein,Jørgen Kjems,Jochen H. M. Prehn,Stephanie Schorge,Kai Lamottke,Felix Rosenow,Felix Rosenow +9 more
TL;DR: The latest findings provide a rich source of new miRNAs that appear to influence seizures or hippocampal pathology, but substantial challenges remain before their role in the pathogenesis, diagnosis, and treatment of epilepsy can be translated into clinical practice.
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A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1
Liron Bar-Peled,Lynne Chantranupong,Andrew D. Cherniack,Walter W. Chen,Kathleen Ottina,Brian C. Grabiner,Eric D. Spear,Scott L. Carter,Matthew Meyerson,David M. Sabatini +9 more
TL;DR: GATOR is identified as a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer.
Journal ArticleDOI
Review: The international consensus classification of Focal Cortical Dysplasia – a critical update 2018
TL;DR: The electro‐clinico‐imaging phenotype and surgical outcomes of FCD type II (in particular type IIb) were further defined and validated, paving the way for the design of an integrated clinico‐pathological and genetic classification system, as recently recommended by the WHO for the classification of malignant brain tumours.
Journal ArticleDOI
Regulation and metabolic functions of mTORC1 and mTORC2
TL;DR: In this article, the authors discuss the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes, highlighting findings from cancer models but also discuss other examples of mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders and aging.
References
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mTOR Signaling in Growth Control and Disease
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
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mTOR signaling in growth control and disease.
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
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Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.
Brinda Ravikumar,Coralie Vacher,Zdenek Berger,Janet E. Davies,Shouqing Luo,Lourdes Garcia Oroz,Francesco Scaravilli,Douglas F. Easton,Rainer Duden,Cahir J. O'Kane,David C. Rubinsztein +10 more
TL;DR: This work shows that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains, and provides proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
Journal ArticleDOI
Molecular mechanisms of mTOR-mediated translational control
Xiaoju Max Ma,John Blenis +1 more
TL;DR: Recent findings on the regulators and effectors of mTOR are highlighted and specific cases that serve as paradigms for the different modes of m TOR regulation and its control of translation are discussed.
Journal ArticleDOI
Regulation of Mammalian Autophagy in Physiology and Pathophysiology
Brinda Ravikumar,Sovan Sarkar,Janet E. Davies,Marie Futter,Moisés García-Arencibia,Zeyn W. Green-Thompson,Maria Jimenez-Sanchez,Viktor I. Korolchuk,Maike Lichtenberg,Shouqing Luo,Dunecan Massey,Fiona M. Menzies,Kevin Moreau,Usha Narayanan,Maurizio Renna,Farah H. Siddiqi,Benjamin R. Underwood,Ashley R. Winslow,David C. Rubinsztein +18 more
TL;DR: This review focuses on mammalian autophagy, and an overview of the understanding of its machinery and the signaling cascades that regulate it is given, and the possibility of autophagic upregulation as a therapeutic approach for various conditions is considered.