Role of mTORC1 Controlling Proteostasis after Brain Ischemia

Abstract

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.

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…mTORC1 is regulated by growth factors that activate the PI3K/Akt signaling pathway, such as IGF-1 and BDNF (Perez-Alvarez et al, 2018), which are involved in the neuroprotective mechanisms of estradiol (see Section 2.13). Estradiol activates the PI3K/Akt/mTORC1 pathway in neurons to promote neuritic growth and it has been proposed that mTORC1 may participate in the neuroprotective mechanisms of estradiol after brain ischemia (Perez-Alvarez et al, 2018) and in the remeyelination induced by the ERβ ligand DPN in an experimental mouse model of multiple sclerosis (Kumar et al, 2013). One of the best characterized functions of mTORC1 is to connect environmental cues, such as nutrient availability, with cellular homeostasis, including the inhibition of autophagy.…”

Rapamycin treatment increases hippocampal cell viability in an mTOR-independent manner during exposure to hypoxia mimetic, cobalt chloride

“…This is not surprising, as mTOR has been reported to decrease in the brain during stressful situations, such as glucose deprivation, DNA damage, and hypoxia [51]. However, as with mTOR in cardiac ischemia, there is still uncertainty as to the role of mTOR in mediating cerebral stroke damage in vivo.…”

Ambiguous Effects of Autophagy Activation Following Hypoperfusion/Ischemia

“…In this respect, it is well-known that ATG is markedly increased during the reperfusion phase, which follows an ischemic insult [ 78 , 79 ]. Furthermore, the authentic functional significance of this increased ATG activity is still under debate, and contradictory data are reported concerning its beneficial or detrimental effects [ 80 , 81 , 82 , 83 ]. ATG proteins and vacuoles increase concomitantly with the apoptotic markers within dying neurons.…”

“…Among these, the cyclic AMP-responsive element binding protein (CREB) is involved in this hypoxic-induced increased expression of protective molecules, such as brain derived neurotrophic factor (BDNF) and bcl2 [ 91 , 143 , 144 , 145 , 146 , 147 ]. Moreover, Akt inhibits Tsc2, leading to mTOR activation and ATG inhibition [ 83 , 139 ] ( Figure 2 ). Therefore, in hypoxic/ischemic conditions, ATG activity is oppositely modulated by the AMPK and Akt pathways through mTOR [ 148 ], which in turn, may determine per se the inhibition of ATG via different mechanisms [ 83 , 149 ].…”