Neurotrophins are initially synthesized as precursor forms that are cleaved to release C-terminal mature forms that bind to Trk receptors to initiate survival and differentiative responses. Recent studies suggest that the precursor form of NGF (proNGF) acts as a distinct ligand by binding to a receptor complex of p75 and sortilin to initiate cell death. Induction of proNGF and p75 has been observed in multiple pathological states and injury models in the central nervous system, and blockade of proNGF/p75 interaction is efficacious in limiting neuronal apoptosis. Multiple strategies that may act to limit proNGF action are considered as potential therapeutic targets for future development.
