Attenuating the endoplasmic reticulum stress response improves functional recovery after spinal cord injury

Abstract

Activation of the unfolded protein response (UPR) is involved in the pathogenesis of numerous CNS myelin abnormalities; yet, its direct role in traumatic spinal cord injury (SCI)-induced demyelination is not known. The UPR is an evolutionarily conserved cell defense mechanism initiated to restore endoplasmic reticulum homeostasis in response to various cellular stresses including infection, trauma, and oxidative damage. However, if uncompensated, the UPR triggers apoptotic cell death. We demonstrate that the three signaling branches of UPR including the PERK, ATF6, and IRE1α are rapidly initiated in a mouse model of contusive SCI specifically at the injury epicenter. Immunohistochemical analyses of the various UPR markers revealed that in neurons, the UPR appeared at 6 and 24-h post-SCI. In contrast, in oligodendrocytes and astroglia, UPR persisted at least for up to 3 days post-SCI. The UPR-associated proapoptotic transcriptional regulator CHOP was among the UPR markers upregulated in neurons and oligodendrocytes, but not in astrocytes, of traumatized mouse spinal cords. To directly analyze its role in SCI, WT and CHOP null mice received a moderate T9 contusive injury. Deletion of CHOP led to an overall attenuation of the UPR after contusive SCI. Furthermore, analyses of hindlimb locomotion demonstrated a significant functional recovery that correlated with an increase in white-matter sparing, transcript levels of myelin basic protein, and Claudin 11 and decreased oligodendrocyte apoptosis in CHOP null mice in contrast to WT animals. Thus, our study provides evidence that the UPR contributes to oligodendrocyte loss after traumatic SCI.

Deletion of the Pro-Apoptotic Endoplasmic Reticulum Stress Response Effector CHOP Does Not Result in Improved Locomotor Function after Severe Contusive Spinal Cord Injury

“…We recently demonstrated activation of the ERSR in a moderate T9 contusion model of SCI, and significant functional recovery in the hindlimb locomotion of CHOP-null mice. That functional recovery correlated with an increase in white matter sparing and transcript levels of myelin basic protein (MBP) and claudin 11 (Ohri et al, 2011). Similarly, a previous study demonstrated ERSR activation in rats after moderate contusive SCI (Penas et al, 2007).…”

“…In addition, a significant increase in CHOP transcript levels was also apparent in rostral segments at 24 and 72 h post-injury, suggesting the spread of the UPR to adjacent tissue. This increase was not observed after moderate contusive SCI (Ohri et al, 2011). A significant 2.5-to 2.8-fold induction of GRP78 mRNA was observed at 12 h post-severe SCI, which increased to 3.2-fold at 24 h, and then decreased to 2.5-to 2.8-fold at 72 h. In contrast, the rostral segments did not show increased expression of GRP78 mRNA except at 72 h. The expression level of GADD34 mRNA increased to 3.5-fold as early as 1 h post-injury, persisted until 12 h, and then declined to basal levels by 72 h. Upregulation of GADD34 transcript levels was specific to the injury epicenter, as the rostral segments did not show any significant upregulation at any of the time points tested (Fig.…”

Endoplasmic reticulum stress response in the rat contusive spinal cord injury model-susceptibility in specific cell types

“…15,16 Although OPCs that are abundant in the adult spinal cord increase in number in response to such stimuli as demyelination and other external injuries, 17 sufficient remyelination in not achieved in contusive SCI models due to differentiation blockage. This is in contrast to chemical demyelination models in which a replenishment of the lost OL pool is observed.…”

“…8,10,19 In SCI, the expression of GRP78 has been histologically confirmed in the damaged tissue of the spinal cord at the acute stage. 7,15 It has been suggested that astrocytes have a unique ER stress response mechanism and a higher degree of response compared with other cell types. 20 In this study, differences in the GRP78 expression ratio were observed between neurons, OPCs, OLs and astrocytes.…”

Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model

“…7 Accumulation of unfolded proteins within the ER lumen can simultaneously lead to the overexpression of glucose-regulated protein 78 (GRP78/BiP) and C/EBP homologous protein (CHOP), and activate the caspase-12, a crucial protein related to cell apoptosis induced by ER stress. 8 Recent studies have revealed that ER stressinduced apoptosis plays an important role in the pathogenesis and development of many diseases. 9 Bifulco et al indicated that the activation of UPR and the alteration of GRP78 expression were involved in endometrial cancer development and progression.…”