Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions

Abstract

The PKR-like endoplasmic reticulum kinase (PERK) pathway of the unfolded protein response (UPR) is protective against toxic accumulations of misfolded proteins in the endoplasmic reticulum, but is thought to drive cell death via the transcription factor, CHOP. However, in many cell types, CHOP is an obligate step in the PERK pathway, which frames the conundrum of a prosurvival pathway that kills cells. Our laboratory and others have previously demonstrated the prosurvival activity of the PERK pathway in oligodendrocytes. In the current study, we constitutively overexpress CHOP in myelinating cells during development and into adulthood under normal or UPR conditions. We show that this transcription factor does not drive apoptosis. Indeed, we observe no detriment in mice at multiple levels from single cells to mouse behavior and life span. In light of these data and other studies, we reinterpret PERK pathway function in the context of a stochastic vulnerability model, which governs the likelihood that cells undergo cell death upon cessation of UPR protection and while attempting to restore homeostasis.

Endoplasmic Reticulum Protein Quality Control Failure in Myelin Disorders

“…Indeed numerous studies carried out in the CNS and the PNS (see below) do not support a role for CHOP in apoptosis, but suggest it should be viewed as a mediator of responses to stress (Gow and Wrabetz, 2009). Consistently, a recent study shows that CHOP overexpression in oligodendrocytes and Schwann cells of wild-type, msd and rsh mice does not influence animal life span or oligodendrocytes apoptosis (Southwood et al, 2016). Interestingly, the authors report that only half of myelinating oligodendrocytes from rsh mice expresses CHOP and propose that myelinating cells expressing PLP mutants alternate periods of active UPR, with subsequent attenuation of protein synthesis, and periods of inactive UPR and increased metabolism, leading to myelin production.…”

“…Interestingly, the authors report that only half of myelinating oligodendrocytes from rsh mice expresses CHOP and propose that myelinating cells expressing PLP mutants alternate periods of active UPR, with subsequent attenuation of protein synthesis, and periods of inactive UPR and increased metabolism, leading to myelin production. In this view, cells switching off the UPR may be more vulnerable to pro-death signals due to the re-activation of the metabolism, such as calcium release or ROS production (Southwood et al, 2016). Further experiments performed at a single-cell level should be performed to confirm this model.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Silencing of CHOP in the rabbit hippocampus protects animals from AD induced by 27-hydroxycholesterol, an oxidized metabolite of cholesterol (Prasanthi et al 2011). In contrast to the apoptotic role of CHOP in AD and PD, constitutive overexpression of CHOP in myelinating cells under normal or ER stress conditions does not drive cell death (Southwood et al 2016). …”

A potential strategy for reducing cysts in autosomal dominant polycystic kidney disease with a CFTR corrector

“…In this model, overexpression of GADD153 did not promote cell death but instead was suggested to be prosurvival through a dynamic regulatory cycle involving the unfold protein response. The higher expression levels of GADD153 in the cystic mice may be another indicator of the prosurvival pathways that allow cysts to grow in the kidney at the expense of healthy tissue (55,56). Thus, its downregulation by VX-809 is likely the result of the reduction in cyst burden.…”