ProBDNF

proBDNF is the precursor form of brain-derived neurotrophic factor (BDNF), a neurotrophin that supports neuronal survival, development, and synaptic plasticity. The BDNF gene is transcribed into a transcript that codes for a pre-proprotein, which is cleaved to produce proBDNF. ProBDNF can be secreted and then converted into mature BDNF by proteolytic processing, or, in some contexts, cleaved intracellularly during synthesis.

Processing of proBDNF involves multiple proteases. Intracellularly, furin-like convertases in the secretory pathway can generate mature BDNF. Extracellularly, enzymes such as plasmin (activated by tissue plasminogen activator, tPA) and certain matrix metalloproteinases can cleave proBDNF to mature BDNF. The relative abundance of proBDNF versus mature BDNF is regulated by neuronal activity and the availability of these proteases, and this balance modulates distinct signaling outcomes.

Signaling pathways diverge for the two forms. proBDNF preferentially binds to the p75 neurotrophin receptor (p75NTR), often in concert with sortilin, to promote signaling that can lead to apoptosis, axonal pruning, or long-term depression of synaptic transmission. By contrast, mature BDNF binds to the TrkB receptor, promoting neuronal survival, dendritic growth, and long-term potentiation of synapses. Thus, the balance between proBDNF and mature BDNF influences synaptic plasticity and neuronal fate.

Dysregulation of proBDNF processing and signaling has been studied in aging and neurodegenerative and psychiatric disorders, including Alzheimer’s disease and major depressive disorder. Research aims to understand how shifting the proBDNF/mature BDNF ratio affects neural function and disease progression.