Necrotic neuronal death underlies the pathology of many neurodegenerative diseases and is an incapacitating outcome of stroke, ischemia, acidosis, and physical injury. Currently, there are no effective clinical treatments that protect against necrotic neuronal loss and understanding of necrosis mechanisms lags far behind understanding of apoptotic death. Extending mechanistic understanding of necrosis is an essential first step toward design of effective interventions. In the facile genetic model C. elegans, hyper-activated mutant plasma membrane ion channels of the DEG/ENAC superfamily conduct excess Na+ and Ca+2 to initiate necrotic neuronal death. Our genetic dissection of this process in nematodes suggests that Ca+2 influx through the MEC DEG/ENaC channel is critical in necrosis initiation, and that the neurotoxicity mechanism requires ER Ca+2 release. The resultant rise in intracellular Ca+2 promotes necrotic demise, acting in part through specific Ca+2-activated calpain proteases and cathepsin proteases associated with lysosomal dysfunction. Although we have made much progress in establishing a genetic pathway for neuronal necrosis, there are major gaps in our mechanistic understanding of necrosis, including the perplexing problem of how MEC channel hyperactivation can circumvent Ca+2 homeostasis mechanisms to signal for toxic ER Ca+2 release. This mechanism appears directly relevant to parallel toxicity mechanisms operative in higher organisms--the MEC channel-related mammalian ASIC1a channel of the DEG/ENaC family can be hyperactivated in stroke to conduct excess Ca+2 influx, inducing acidosis and substantial brain neuron loss. Intracellular Ca+2 rise and activation of calpain proteases are features of human necrosis, suggesting death mechanisms are conserved from nematodes to humans. Our experimental plan is to combine genetic, molecular biological and Ca+2 imaging approaches to define key conserved players in neuronal necrosis, and to determine where and how they act in the necrotic pathway. We have identified novel necrosis-enhancing mutants (normal activity protects against necrosis) and calcium binding protein genes that modulate necrosis outcomes-- these constitute the foundation for our planned mechanistic investigations. Overall, we expect to exploit unique advantages of the C. elegans experimental model to generate a detailed mechanistic description of necrosis, including identification of novel genetic factors that may suggest new strategies for limiting devastating effects of necrosis in human injury and disease.
Stroke, ischemia, acidosis, physical injury to neurons, and neurodegenerative disease can induce a type of neuronal death called necrosis. Necrotic neuronal loss is a thus major clinical problem--yet there are currently no effective treatments that combat neuronal necrosis, in part because necrosis mechanisms are not well defined. We work with a simple genetic animal model for channel hyperactivation-induced necrosis to identify genes that are essential for, promote, or diminish neuronal necrosis. There is strong evidence that necrosis mechanisms are conserved from simple animals to humans (for example, the mammalian homolog of the channel we study is a major contributor to neuronal loss in mouse stroke models). Molecularly identifying necrosis modulator genes and determining how they work to affect necrosis outcomes will provide much needed understanding of basic necrosis mechanisms and should inspire novel approaches toward potential anti-necrosis therapies.
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