During the normal development of the mammalian nervous system nearly half of the neurons undergo apoptosis as part of a natural pruning process. Dysfunctional apoptosis has been associated with a variety of neurological diseases such as Alzheimer's, Huntington's and Parkinson's diseases, ALS and multiple system atrophy. The critical balance between necessary cell death and maintenance of essential neurons is controlled by the neurotrophins. Their effects are mediated through binding to a family of tyrosine kinase receptors, the Trks, and a 75-kD receptor, p75. It has been shown that the Trks activate canonical growth factor receptor signaling pathways. In contrast, the function of p75 remains largely unexplored. Recent evidence suggests that ligand binding to p75 in specific cell types can activate the transcription factor NFkappaB and induce apoptosis through a mechanism involving jun kinase. The activation of programmed cell death by classical trophic factors is somewhat surprising, especially given the widespread expression of both p75 and the neurotrophins throughout the nervous system. Clearly, the activation of apoptosis must be highly regulated such that it only occurs in specific contexts. The overall goal of this research proposal is to understand the molecular mechanisms by which the neurotrophins regulate neuronal survival, in particular, signaling through the p75 receptor. Currently there are no known receptor-associated proteins that transduce p75's signal. This proposal describes a novel zinc finger protein, NRIF, isolated using the yeast two hybrid system, which binds to the cytoplasmic domain of p75 in a ligand-dependent manner. This proposal will test the hypothesis that neurotrophin binding to p75 activates a signal transduction pathway that promotes both cell survival and programmed cell death mediated in part by the novel p75 interactor NRIF. To test this hypothesis the following specific aims are proposed: (1) Define the domains of NRIF and p75 responsible for their interaction; (2) Determine the molecular components of p75 signaling; (3) Assess the mechanisms by which p75 regulates cell survival. Understanding neurotrophin signaling mechanisms will provide insight into how these essential factors regulate the development of the vertebrate nervous system and could suggest novel strategies for therapeutic intervention in neurological disorders.
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