ProNGF processing in adult rat tissues and bioactivity of NGF prodomain peptides

• Published in: FEBS open bio 2024-04, Vol.14 (4), p.643-654
• Main Authors: Makoudjou, Marie Anne, Fico, Elena, Rosso, Pamela, Triaca, Viviana, De Simone, Lucio, Rossetti, Daniela, Cattani, Franca, Allegretti, Marcello, Tirassa, Paola
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Biological activity; Brain; Growth factors; Hippocampus; Homeostasis; Inflammation; Investigations; Kinases; Lipopolysaccharides; Nerve growth factor; Peptides; Physiology; prodomain; proNGF; Proteins
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13768

The neurotrophin nerve growth factor (NGF) and its precursor proNGF are both bioactive and exert similar or opposite actions depending on the cell target and its milieu. The balance between NGF and proNGF is crucial for cell and tissue homeostasis and it is considered an indicator of pathological conditions. Proteolytical cleavage of proNGF to the mature form results in different fragments, whose function and/or bioactivity is still unclear. The present study was conducted to investigate the distribution of proNGF fragments derived from endogenous cleavage in brain and peripheral tissues of adult rats in the healthy condition and following inflammatory lipopolysaccharide (LPS) challenge. Different anti‐proNGF antibodies were tested and the presence of short peptides corresponding to the prodomain sequence (pdNGFpep) was identified. Processing of proNGF was found to be tissue‐specific and accumulation of pdNGFpeps was found in inflamed tissues, mainly in testis, intestine and heart, suggesting a possible correlation between organ functions and a response to insults and/or injury. The bioactivity of pdNGFpep was also demonstrated in vitro by using primary hippocampal neurons. Our study supports a biological function for the NGF precursor prodomain and indicates that short peptides from residues 1–60, differing from the 70–110 sequence, induce apoptosis, thereby opening the way for identification of new molecular targets to study pathological conditions. The balance and interaction of TrkA/p75NTR with proNGF and its related cleavage product NGF and pdNGFpeps play a pivotal role in the maintenance of structural and functional integrity of target organs. Imbalance of NGF and pdNGFpeps triggered by inflammation as well as deafferentation might activate apoptosis signals and contribute to insurgence and progression of organ damage and disease.