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A Novel Vertebral Stabilization Method for Producing Contusive Spinal Cord Injury
Published on: January 5, 2015
Zbtb38 is a novel target for spinal cord injury
Yafei Cai1,2,3, Jun Li2, Zongmeng Zhang2
1College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
Abstract:
Spinal cord injury (SCI) is currently incurable since treatments applied to clinic are limited to minimizing secondary complications and the mechanisms of injury-induced spinal cord damage are poorly understood. Zbtb38, also called CIBZ, is highly expressed in spinal cord and it functions as a negative regulator in SCI-induced apoptosis. We show here that Zbtb38 is downregulated under endoplasmic reticulum (ER) stress, which promotes ER stress-associated apoptosis in human bone marrow neuroblastoma cells. In the traumatic SCI mice, ER stress presented in injured spinal cord induced repression of Zbtb38 expression and triggered Zbtb38-mediated apoptosis. ChIP-QPCR analysis revealed that ATF4, an ER-stress inducible transcription factor, directly activated Zbtb38 transcription by binding to the Zbtb38 promoter. However, this binding was significantly reduced following SCI, leading to a sharp decrease in Zbtb38 expression. Restoring Zbtb38 function in injured spinal cord by injection of lentivirus containing Zbtb38 into SCI mice, significantly alleviated secondary damage of spinal cord with decreased ER stress-associated apoptosis and partially recovered spinal cord functions. These findings demonstrate that restoration of Zbtb38 expression can reduce secondary tissue damage after SCI, and suggest that a therapeutic strategy for targeting Zbtb38 may promote functional recovery of spinal cord for patients with SCI.
Insights
Restoring Zbtb38 expression in spinal cord injury (SCI) mice reduced secondary damage and apoptosis by alleviating endoplasmic reticulum (ER) stress. This suggests Zbtb38 as a potential therapeutic target for SCI functional recovery.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- Spinal cord injury (SCI) remains incurable, with limited treatments focusing on secondary complications.
- Understanding the mechanisms of SCI-induced damage is crucial for developing effective therapies.
- Zbtb38 (CIBZ) is a negative regulator of apoptosis in the spinal cord.
Purpose of the Study:
- To investigate the role of Zbtb38 in endoplasmic reticulum (ER) stress-associated apoptosis following SCI.
- To explore Zbtb38 as a potential therapeutic target for mitigating SCI-induced damage and promoting functional recovery.
Main Methods:
- Investigated Zbtb38 expression under ER stress in neuroblastoma cells.
- Analyzed Zbtb38 downregulation and apoptosis in traumatic SCI mouse models.
- Utilized ChIP-QPCR to examine the interaction between ATF4 and the Zbtb38 promoter.
- Administered lentivirus-mediated Zbtb38 restoration in SCI mice.
Main Results:
- Zbtb38 is downregulated under ER stress, promoting apoptosis.
- SCI induces ER stress, repressing Zbtb38 expression and triggering apoptosis.
- ATF4 directly activates Zbtb38 transcription, but this binding is reduced post-SCI.
- Restoring Zbtb38 alleviated secondary damage, reduced ER stress-associated apoptosis, and partially recovered function in SCI mice.
Conclusions:
- Zbtb38 downregulation under ER stress contributes to SCI-induced apoptosis.
- Restoration of Zbtb38 expression mitigates secondary damage and enhances functional recovery after SCI.
- Targeting Zbtb38 presents a promising therapeutic strategy for SCI treatment.
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