How do oligodendrocytes and neurons protect themselves from the effects of inflammation? Can the cellular stress response be enhanced to increase protection?

Project: Research project

Project Details

Description

The unfolded protein response (UPR) is activated in multiple sclerosis (MS) lesions and in the preclinical MS animal model-experimental autoimmune encephalomyelitis (EAE) (1,2). The UPR is an adaptive cytoprotective response that is orchestrated by three transmembrane UPR signal transducers: inositol requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and PKR-like endoplasmic reticulum kinase (PERK) (3). Activated PERK phosphorylates eIF2α, leading to the rapid attenuation of cap-dependent translation while simultaneously triggering translation of stress responsive genes, including ATF4. As the center of the integrated stress response pathway (ISR), phosphorylated eIF2α (p-eIF2α) is eventually dephosphorylated by protein phosphatase 1 (PP1) along with its cofactor growth arrest and DNA-damage inducible 34 (GADD34), resulting in cessation of the ISR and restoration of protein homeostasis (4) (Fig 1). We have demonstrated that the ISR plays a key role in the protection of oligodendrocytes (OLs) in response to CNS inflammation: genetic manipulations that compromise the ISR increase susceptibility to CNS inflammation and the genetic enhancement of the ISR (5,6), provides increased CNS protection against inflammation (7,8). Here, we propose to investigate the impact of the IRE and ATF6 branches of the UPR on the OL protection and continue to determine whether enhancing the ISR can protect remyelinating OLs during inflammation. We will also further characterize the molecular changes in the OLs in the presence of inflammation.
StatusActive
Effective start/end date10/10/199/30/21

Funding

  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (04-7023433)

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