Apoptosis, or programmed cell death, is fundamental to the development and maintenance of multi-cellular organisms. It is required for sculpting complex tissue architectures, and for the productive matching of cells during development of the nervous and immune system. p75/NTR, the common neurotrophin receptor, has been demonstrated as a pro-apoptotic gene at certain neural development stages in the absence of NGF binding. In the presence of NGF (a dimer molecule), this effect is inhibited. In the past few years, the molecular mechanisms of p75/NTR inducing apoptosis hs been extensively studied; however, the molecular mechanism of p75/NTR upon ligand binding which blocks apoptosis, demands further investigation. The primary goal of this proposal is to determine whether the p75/NTR dimer can block apoptosis in neuronal cells, in comparison to the monomer effect. The next step is to identify an intracellular protein which interacts with the intracytoplasmic domain of p75/NTR dimer, versus the monomer. The information gained by these studies should be relevant to the TNFR superfamily, and therefore will contribute towards understanding the mechanisms of the signal transduction of apoptosis by other cell surface receptors. Furthermore, the function of p75/NTR has been linked to the pathogenesis of Alzheimer's disease; understanding the mechanism of p75/NTR apoptosis control is important for continuing the search for causes and cures of neurodegenerative diseases.
