Why are hippocampal CA1 neurons vulnerable but motor cortex neurons resistant to transient ischemia?
It is well-known that heat-shock protein 70.1 (Hsp70.1), a major protein of the human Hsp70 family, plays cytoprotective roles by both its chaperone function and stabilization of lysosomal membranes. Recently, we found that calpain-mediated cleavage of carbonylated Hsp70.1 in the hippocampal cornu Ammonis1 (CA1) contributes to neuronal death after transient global ischemia. This study aims to elucidate the differential neuronal vulnerability between the motor cortex and CA1 sector against ischemia/reperfusion. Fluoro-Jade B staining and terminal deoxynucleotidyl transferase-mediated dUTP-nick-end-labeling analysis of the monkey brain undergoing 20min whole brain ischemia followed by reperfusion, showed that the motor cortex is significantly resistant to the ischemic insult compared with CA1. Up-regulation of Hsp70.1 but absence of its cleavage by calpain facilitated its binding with NF-κB p65/IκBα complex to minimize NF-κB p65 activation, which contributed to a neuroprotection in the motor cortex. In contrast, because activated μ-calpain cleaved carbonylated Hsp70.1 in CA1, the resultant Hsp70.1 dysfunction not only destabilized lysosomal membrane but also induced a sustained activation of NF-κB p65, both of which resulted in delayed neuronal death. We propose that the cascades underlying lysosomal stabilization and regulating NF-κB activation by Hsp70.1 may influence neuronal survival/death after the ischemia/reperfusion.
Department of Restorative Neurosurgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Hong
H
Zhu
Tanihiro
T
Yoshimoto
Shinobu
S
Imajo-Ohmi
Maryia
M
Dazortsava
Arumugam
A
Mathivanan
Tetsumori
T
Yamashima
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology*; D008251:Macaca; D009044:Motor Cortex / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000502:physiology
D018840:HSP70 Heat-Shock Proteins; C081884:heat-shock protein 70.1