Inhibition of GADD34, the stress-inducible regulatory subunit of the endoplasmic reticulum stress response, does not enhance functional recovery after spinal cord injury.
Activation of the endoplasmic reticulum stress response (ERSR) is a hallmark of various pathological diseases and/or traumatic injuries. Restoration of ER homeostasis can contribute to improvement in the functional outcome of these diseases. Using genetic and pharmacological inhibition of the PERK-CHOP arm of the ERSR, we recently demonstrated improvements in hindlimb locomotion after spinal cord injury (SCI) and implicated oligodendrocyte survival as a potential mechanism. Here, we investigated the contribution of stress-inducible PPP1R15A/GADD34, an ERSR signaling effector downstream of CHOP that dephosphorylates eIF2α, in the pathogenesis of SCI. We show that although genetic ablation of GADD34 protects oligodendrocyte precursor cells (OPCs) against ER stress-mediated cell death in vitro and results in differential ERSR attenuation in vivo after SCI, there is no improvement in hindlimb locomotor function. Guanabenz, a FDA approved antihypertensive drug, was recently shown to reduce the burden of misfolded proteins in the ER by directly targeting GADD34. Guanabenz protected OPCs from ER stress-mediated cell death in vitro and attenuated the ERSR in vivo after SCI. However, guanabenz administration failed to rescue the locomotor deficits after SCI. These data suggest that deletion of GADD34 alone is not sufficient to improve functional recovery after SCI.
Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, United States of America; Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, United States of America.
Sujata Saraswat
SS
Ohri
Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, United States of America; Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, United States of America.
Ashley
A
Mullins
Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, United States of America; Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, United States of America; Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky, United States of America; Department of Anatomical Sciences & Neurobiology, University of Louisville, Louisville, Kentucky, United States of America.
Michal
M
Hetman
Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, United States of America; Department of Neurological Surgery, University of Louisville, Louisville, Kentucky, United States of America; Department of Anatomical Sciences & Neurobiology, University of Louisville, Louisville, Kentucky, United States of America.
Scott R
SR
Whittemore
D058647:Adrenergic alpha-2 Receptor Agonists / Q000627:therapeutic use; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006143:Guanabenz / Q000627:therapeutic use*; D008124:Locomotion / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000166:cytology; D010766:Phosphorylation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D013234:Stem Cells / Q000166:cytology; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors
D058647:Adrenergic alpha-2 Receptor Agonists; D006143:Guanabenz; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D051742:Transcription Factor CHOP; D014415:Tunicamycin; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C531557:eIF2alpha kinase, mouse; C513256:Ppp1r15a protein, mouse