title: 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.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky 40292, USA.
authors.forename: Sujata Saraswat
authors.initials: SS
authors.lastname: Ohri
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Maddie
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Mengsheng S
authors.initials: MS
authors.lastname: Qiu
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
authors.forename: Scott R
authors.initials: SR
authors.lastname: Whittemore
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000172:deficiency; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
chemical_list: D051701:Activating Transcription Factor 4; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; C497250:Ddit3 protein, mouse; C512773:Olig2 protein, mouse