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Activation of the mTOR pathway in astrocytes after spinal cord ischemia

  • Author(s): Codeluppi, Simone
  • et al.
Abstract

Spinal cord injury is characterized by cell death, macrophage infiltration, and formation of a glial scar. Functional recovery from this severe damage is dependent on the regeneration and growth of the axons of the surviving neurons beyond the lesion site and on the formation of the proper synaptic connections between the axons and their targets. However, the regeneration process is affected by inhibitory molecules expressed by the astrocytes of the glial scar and derived from the rupture of the myelin sheats. A better environment for spinal cord regeneration can be created by regulating glial scar formation and by blocking the effects of the myelin derived inhibitors. In the adult central nervous system, epidermal growth factor (EGF) regulates astrocyte activation and scar formation. Inhibition of EGF receptor signaling showed beneficial effects and promoted functional recovery and locomotion in an animal model of contusion-induced spinal cord injury. We showed that EGF receptor activates the mammalian target of rapamycin (mTOR) pathway in primary cultures of adult spinal cord astrocytes. EGF receptor activation causes Akt mediated phosphorylation and downregulation of the mTOR pathway inhibitor Tuberin. Since Tuberin is a GTPase-activating protein that regulates the activity of the small GTPase Rheb, EGF treatment increases Rheb and mTOR activity. Furthermore, in primary cultures of spinal cord astrocytes, mTOR regulates proliferation and EGF-induced migration. We also detected increased activation of the EGF receptor and the mTOR pathway in hypertrophic astrocytes in the spinal cord after ischemia-induced injury. These in vitro and in vivo findings suggest that EGF-induced astrocyte hypertrophy is regulated by the mTOR pathway. Inhibition of mTOR activity with rapamycin may reduce astrocyte hypertrophy as well as scar formation and prove beneficial for axonal regeneration and functional recovery after spinal cord injury

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