Regulation of proNGF processing and its effects on p75NTR-mediated cell death following seizure

Nerve growth factor (NGF) has been known to play critical roles in neuronal survival and differentiation during development. Recent studies have discovered that its immature form, proNGF, is a ligand for the p75 neurotrophin receptor (p75NTR). proNGF binding to p75NTR activates apoptotic signaling, and this binding occurs with a five-fold higher affinity than that of mature NGF (Lee et al., 2001). This binding preference, along with the increased prevalence of proNGF after injury (Harrington et al., 2004), creates a cellular environment susceptible to cell death; thus, the balance between levels of pro- and mature NGF may be a key factor in determining whether a neuron lives or dies (Lee et al., 2001; Volosin et al., 2006). Using both in vitro and in vivo methods, this thesis examined the mechanisms that regulate the extracellular processing of proNGF and the consequences of that processing on p75NTR-mediated cell death following injury. The results discussed here demonstrate that 1) proNGF binding leads to cell death via the p75NTR signaling pathway; 2) after injury, proNGF is upregulated and preferentially secreted in a functional manner capable of activating the p75NTR-mediated apoptotic pathway; 3) the enzymes plasmin and MMP7 extracellularly cleave proNGF, 4) after injury, plasmin activation and MMP7 activity are reduced, leading to increased proNGF-induced apoptosis, and 5) restoring plasmin or MMP7 activity following brain injury reduces proNGF levels and consequently, p75NTR-mediated apoptosis. Overall, these data suggest that increased cell death following injury may be mediated in part by a change in the balance between extracellular proNGF and the activity of its processing enzymes, leading to increased cell death via p75NTR.Ph.D.Includes bibliographical referencesIncludes vitaby Audrey P. L