Hsp70.1 and related lysosomal factors for necrotic neuronal death

Necrosis has long been considered accidental and uncontrolled, but during the last decade, it became clear that necrosis is also a well-orchestrated form of cell demise, being as well programmed as apoptosis. To explain the mechanism of neuronal necrosis after ischemia/reperfusion, the 'calpain-cathepsin hypothesis' formulated in 1998 postulates that the post-ischemic μ-calpain activation compromises integrity of the lysosomal membrane, thereby leading to cathepsin spillage. Another cause of the lysosomal rupture occurring during reperfusion is reactive oxygen species (ROS) that generate 4-hydroxy-2-nonenal (HNE) by oxidation of membrane fatty acids such as linoleic and arachidonic acids. HNE is an endogenous neurotoxin, because HNE-induced carbonylation of the substrate protein shows loss of its function. However, the molecular mechanisms of lysosomal membrane breakdown are still poorly understood; especially, the biochemical cascade how μ-calpain and ROS work together to disrupt lysosomal membrane has remained unclarified. Three independent proteomic analyses of cerebral ischemia, glaucoma, or mild cognitive impairment in primates have altogether suggested that the common substrate of calpain and/or ROS is heat-shock protein 70.1 (Hsp70.1; simply Hsp70, also called Hsp72 or HSPA1), a major protein of the human Hsp70 family. Hsp70.1 serves cytoprotective roles as a guardian of the lysosomal membrane integrity by assisting sphingomyelin degradation or maintaining proper protein folding and recycling as a chaperone. However, calpain-mediated cleavage of Hsp70.1, especially after its carbonylation because of the oxidative stresses, can induce lysosomal rupture. Furthermore, Hsp70.1 dysfunction activates nuclear factor-kappaB (NF-κB) signaling that can also promote neurodegeneration. By focusing on Hsp70.1 and related lysosomal factors, this review describes rationale of lysosomal destabilization and rupture for executing programmed neuronal necrosis.