proneurotrophins

Proneurotrophins are the precursor molecules of neurotrophins, consisting of a mature neurotrophin sequence linked to an N-terminal pro-domain. The principal proneurotrophins are proNGF, proBDNF, proNT-3, and proNT-4/5. They are synthesized in neurons and other cell types and must be proteolytically processed to generate mature neurotrophins, which differ in receptor affinity and biological activity.

Proteolytic processing occurs intracellularly by convertases such as furin-like enzymes in the Golgi network, and extracellularly by plasmin or matrix metalloproteinases. Depending on the context, proneurotrophins can be secreted and then cleaved, or cleaved before secretion. Mature neurotrophins preferentially activate Trk receptors (TrkA for NGF, TrkB for BDNF and NT-4, TrkC for NT-3), promoting neuronal survival, growth, and synaptic plasticity. In contrast, proneurotrophins tend to signal through a receptor complex comprising p75NTR and sortilin, often supporting apoptosis or synaptic weakening, thereby providing antagonistic or modulatory signals relative to mature neurotrophins.

Biological roles: during development, proneurotrophins contribute to patterning and cell fate decisions; in the adult nervous system they participate in plasticity, regeneration, and response to injury. The relative levels of pro- and mature neurotrophins can shape outcomes in disease and stress.

Clinical and research relevance: altered proneurotrophin signaling has been implicated in neurodegenerative conditions, mood disorders, and traumatic brain injury. In several disorders, elevated proNGF or proBDNF relative to mature forms may contribute to neurodegeneration or maladaptive plasticity. Ongoing research aims to understand regulation of processing, release, and receptor signaling and to explore therapeutic strategies that modulate the balance between proneurotrophins and mature neurotrophins.