Necrotic cell death that accompanies brain injury and oxygen deprivation injures or kills many each year. Despite this critical role in human health, we know very little about the genetic factors regulating necrotic cell death. We and others have identified members of a family of genes, called degenerins, which can mutate to induce necrotic-like death of specific groups of neurons in the easily studied nematode Caenorhabditis elegans. Other genes can also mutate, or be engineered, to induce necrotic-like cell death that is distinct from apoptosis. Our initial studies suggest that C. elegans cell may mount a common injury response to distinct toxic insults, which can result in necrotic-like cell death. This presents the opportunity to decipher in molecular detail how misregulation of ion channel activity (and other insults) induces necrosis and to define the molecular events that transpire during neurodegeneration. We propose to exploit the powerful molecular genetics of C. elegans to identify molecules that initiate and execute this degenerative cell death. In complementary studies, we plan to investigate cellular changes that accompany neuronal demise. More specifically, we will: 1) clone and characterize a novel gene that can mutate to induce necrosis; 2) genetically characterize death suppressor mutations; 3) determine the molecular identities of key death suppressor genes. We will also catalog changes in compartmentalized proteins and [Ca++] that occur during necrotic cell death and test hypotheses concerning the nature of whorl-like figures that accumulate in dying cells and distinguish this type of cell death. The proposed work is important to heath related issues in that it will advance understanding of basic cellular and molecular events accompanying necrotic-like cell death. The death mechanism we decipher may inspire novel strategies for the prevention of injury-induced cell death.