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

Autor: Scott R. Whittemore, Melissa A. Maddie, Sujata Saraswat Ohri, Yongmei Zhao, Mengsheng S. Qiu, Michal Hetman
Rok vydání: 2011
Předmět:
Time Factors
Oligodendrocyte Transcription Factor 2
Eukaryotic Initiation Factor-2
Apoptosis
CHOP
Nerve Fibers
Myelinated
Mice
Myelin
Basic Helix-Loop-Helix Transcription Factors
Mice
Knockout
Transcription Factor CHOP
Caspase 3
Endoplasmic Reticulum Stress
Up-Regulation
Cell biology
DNA-Binding Proteins
Oligodendroglia
medicine.anatomical_structure
Neurology
Female
biological phenomena
cell phenomena
and immunity
Locomotion
endocrine system
Nerve Tissue Proteins
Regulatory Factor X Transcription Factors
Biology
digestive system
Article
Cellular and Molecular Neuroscience
medicine
Animals
RNA
Messenger
Spinal Cord Injuries
Analysis of Variance
ATF6
Myelin Basic Protein
Recovery of Function
Activating Transcription Factor 4
Oligodendrocyte
Myelin basic protein
Mice
Inbred C57BL
Disease Models
Animal
biological sciences
Unfolded Protein Response
Unfolded protein response
biology.protein
Neuroscience
Transcription Factors
Zdroj: Glia. 59:1489-1502
ISSN: 0894-1491
Popis: 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.
Databáze: OpenAIRE
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