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JNK activation contributes to DP5 induction and apoptosis following traumatic spinal cord injury
Ke-Jie Yin1, Gyeong-Moon Kim, Jin-Moo Lee
1Department of Neurology and Center for the Study of Nervous System Injury (CSNSI), Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Growing evidence suggests that cells undergo apoptosis after spinal cord injury (SCI). However, little is known about the early events that trigger apoptosis in the contused cord. The BH3-only subfamily of pro-apoptotic regulators (e.g., bim, bad, and dp5) is recognized as initiators of the apoptotic cascade, and is subject to stringent control, both at the transcriptional and post-translational level. In the current study, we studied upstream events regulating trauma-induced apoptosis in the spinal cord. Within 1 h after SCI in rats, DP5 was induced, while Bim and Bad levels remained unchanged. In parallel, SCI also activated the stress-induced c-Jun N-terminal kinase (JNK), leading to the phosphorylation of c-Jun, with a similar temporal profile. Immunohistochemical analysis revealed that p-JNK and DP5 colocalized to neurons and oligodendrocytes undergoing apoptosis in the injured cord, but were absent in uninjured spinal cord. Furthermore, inhibition of JNK activity with in vivo delivery of SP600125 or a jnk1 antisense oligodeoxynucleotide (ODN) attenuated DP5 induction and caspase-3 activation. These results suggest that JNK activation contributes to trauma-induced DP5 expression and subsequent apoptosis in SCI.
Insights
Spinal cord injury (SCI) triggers apoptosis through the BH3-only protein DP5. Stress-activated JNK signaling initiates DP5 expression, leading to neuronal and oligodendrocyte cell death after SCI.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Apoptosis (programmed cell death) is increasingly recognized after spinal cord injury (SCI).
- The early molecular triggers of apoptosis in the contused spinal cord remain poorly understood.
- BH3-only proteins, such as DP5, Bim, and Bad, are key initiators of the apoptotic cascade.
Purpose of the Study:
- To investigate the upstream molecular events regulating trauma-induced apoptosis in the spinal cord.
- To identify the role of stress-activated kinases in initiating apoptosis following SCI.
Main Methods:
- Spinal cord injury (SCI) was induced in a rat model.
- Levels of DP5, Bim, and Bad were measured within 1 hour post-injury.
- Activation of c-Jun N-terminal kinase (JNK) and phosphorylation of c-Jun were assessed.
- Immunohistochemistry was used to localize p-JNK and DP5.
- JNK activity was inhibited using SP600125 or jnk1 antisense oligodeoxynucleotide (ODN).
Main Results:
- DP5 expression was rapidly induced within 1 hour after SCI, while Bim and Bad levels were unchanged.
- SCI activated the stress-induced JNK pathway, leading to c-Jun phosphorylation with a similar temporal profile.
- p-JNK and DP5 were found in apoptotic neurons and oligodendrocytes at the injury site.
- Inhibition of JNK activity significantly reduced DP5 induction and caspase-3 activation.
Conclusions:
- JNK activation plays a critical role in the early induction of DP5 following SCI.
- JNK-mediated DP5 expression contributes to trauma-induced apoptosis in neurons and oligodendrocytes.
- Targeting JNK signaling may offer a therapeutic strategy to mitigate cell death after SCI.
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