PreproBDNF

PreproBDNF is the initial translation product of the brain-derived neurotrophic factor (BDNF) gene. It contains an N-terminal signal peptide (the “pre” segment) that directs the protein into the secretory pathway, followed by a pro-domain (the “pro” segment). The mature BDNF peptide is produced when these initial segments are removed by proteolytic processing.

Proteolytic processing of preproBDNF occurs through multiple pathways. In the secretory pathway, proBDNF can be cleaved by proprotein convertases such as furin, PC1/3, or PC2 to generate mature BDNF. In other contexts, extracellular proteases such as plasmin or matrix metalloproteinases can convert proBDNF to mature BDNF after secretion. Depending on the processing route, proBDNF itself or the pro-domain can be released as separate peptides. The pro-domain and mature BDNF can thus have distinct biological roles.

Functional roles differ between the mature and pro forms of BDNF. Mature BDNF binds to the TrkB receptor, promoting neuronal survival, dendritic growth, synaptic plasticity, and activity-dependent learning and memory. By contrast, proBDNF preferentially engages the p75NTR receptor (often with sortilin) and is associated with signaling pathways that can lead to apoptosis or long-term depression of synapses. The balance between mature BDNF and proBDNF, influenced by neuronal activity and cellular context, shapes synaptic strength and plasticity.

Regulation of preproBDNF expression is complex, involving multiple promoters and activity-dependent signaling. Alterations in BDNF processing or levels have been implicated in various neuropsychiatric and neurodegenerative disorders, making the preproBDNF–BDNF maturation axis a focus of neuroscience research.