Mid-Term Report Summary - P75NTR (Understanding death-receptor signaling and physiology in the nervous system: A roadmap for the development of new treatments to neurodegenerative diseases and neurotrauma)
The main objective of this research is to elucidate the molecular mechanisms and physiological relevance of death-receptor signaling in the nervous system and to harness this knowledge for the development of novel treatments to neurodegenerative diseases and neurotrauma. The main focus has been on the p75 neurotrophin receptor (p75NTR), a member of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) predominantly expressed in the developing nervous system and which is highly induced upon different types of neural injury. We have discovered differential p75NTR signaling in different populations of neurons in the brain. This finding has brought greater understanding on the mechanisms by which this receptor affects neuronal cell death. We have elucidated several 3-dimensional structures of protein complexes between p75NTR and intracellular adaptor molecules. This has given us unique insights into the dynamics of the signaling functions of this receptor and clarified the underlying logic. We have generated a number of lines of mutant mice carrying specific lesions in the gene encoding p75NTR and tested hypotheses about oligomerization and structure-function relationships in this receptor in a mouse model of human epilepsy and in cultured neurons. This work has firmly established that, both in vitro and in vivo, neuronal death induced by p75NTR requires the DD and TM Cys259, supporting the physiological relevance of DD signaling by disulfide-linked dimers of p75NTR in the mammalian brain.