Role of mTORC1 Controlling Proteostasis after Brain Ischemia
Entity
UAM. Departamento de BiologíaPublisher
Frontiers MediaDate
2018-02-15Citation
10.3389/fnins.2018.00060
Frontiers in Microbiology 12 (2018): 60
ISSN
1662-4548 (print); 1662-453X (electronic)DOI
10.3389/fnins.2018.00060Project
info:eu-repo/grantAgreement/EC/FP7/CT222887; Gobierno de España. SAF2015-70368- REditor's Version
https://www.frontiersin.org/articles/10.3389/fnins.2018.00060/fullSubjects
signaling, PI3K-Akt, autophagy, stroke, neuroinflammation, neuronal stress response, glia stress response, MCAO; Biología y Biomedicina / BiologíaRights
Copyright © 2018 Perez-Alvarez, Villa Gonzalez, Benito-Cuesta and WandosellAbstract
Intense efforts are being undertaken to understand the pathophysiological mechanisms
triggered after brain ischemia and to develop effective pharmacological treatments.
However, the underlying molecular mechanisms are complex and not completely
understood. One of the main problems is the fact that the ischemic damage is
time-dependent and ranges from negligible to massive, involving different cell types
such as neurons, astrocytes, microglia, endothelial cells, and some blood-derived cells
(neutrophils, lymphocytes, etc.). Thus, approaching such a complicated cellular response
generates a more complex combination of molecular mechanisms, in which cell death,
cellular damage, stress and repair are intermixed. For this reason, animal and cellular
model systems are needed in order to dissect and clarify which molecular mechanisms
have to be promoted and/or blocked. Brain ischemia may be analyzed from two different
perspectives: that of oxygen deprivation (hypoxic damage per se) and that of deprivation
of glucose/serum factors. For investigations of ischemic stroke, middle cerebral artery
occlusion (MCAO) is the preferred in vivo model, and uses two different approaches:
transient (tMCAO), where reperfusion is permitted; or permanent (pMCAO). As a
complement to this model, many laboratories expose different primary cortical neuron
or neuronal cell lines to oxygen-glucose deprivation (OGD). This ex vivo model permits
the analysis of the impact of hypoxic damage and the specific response of different cell
types implicated in vivo, such as neurons, glia or endothelial cells. Using in vivo and
neuronal OGD models, it was recently established that mTORC1 (mammalian Target of
Rapamycin Complex-1), a protein complex downstream of PI3K-Akt pathway, is one of
the players deregulated after ischemia and OGD. In addition, neuroprotective intervention
either by estradiol or by specific AT2R agonists shows an important regulatory role for
the mTORC1 activity, for instance regulating vascular endothelial growth factor (VEGF)
levels. This evidence highlights the importance of understanding the role of mTORC1
in neuronal death/survival processes, as it could be a potential therapeutic target.This
review summarizes the state-of-the-art of the complex kinase mTORC1 focusing in
upstream and downstream pathways, their role in central nervous system and their
relationship with autophagy, apoptosis and neuroprotection/neurodegeneration after
ischemia/hypoxia
Files in this item
Google Scholar:Pérez Álvarez, María José
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Villa González, Mario
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Benito Cuesta, Irene
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Wandosell, Francisco
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