Figure 6: Flow-chart of the possible molecular cascade of neuronal death. Ischemic neurons exhibit perturbed cellular Ca2+ homeostasis, and increased generation of reactive oxygen species (ROS) due to the long-standing, mild cerebral ischemia associated with arteriosclerosis. It is likely that μ-calpain activation, rather than the oxidative modification, is a principal causative factor determining the proteolytic susceptibility of Hsp70.1. The ‘calpain-mediated cleavage of carbonylated Hsp70.1’ is a central event for the development of neuronal death. Hydroxynonenal (HNE) is a membrane lipid-derived neurotoxin that carbonylates Hsp 70.1 to induce more efficient cleavage by activated μ-calpain. Hsp70.1 breakdown induces down-regulation of BMP, which leads to lysosomal destabilization. The latter appears as granulovacuolar degenerations on light microscopy and lysosomal vesiculosis on electron microscopy.
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