The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides
Irina Naletova,
Cristina Satriano,
Adriana Pietropaolo,
Fiorenza Gianì,
Giuseppe Pandini,
Viviana Triaca,
Giuseppina Amadoro,
Valentina Latina,
Pietro Calissano,
Alessio Travaglia,
Vincenzo Giuseppe Nicoletti,
Diego La Mendola,
Enrico Rizzarelli
Affiliations
Irina Naletova
Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Cristina Satriano
Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Adriana Pietropaolo
Department of Health Sciences, University of Catanzaro, Campus Universitario Viale Europa, 88100 Catanzaro, Italy
Fiorenza Gianì
Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, via Palermo n. 636, 95122 Catania, Italy
Giuseppe Pandini
Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, via Palermo n. 636, 95122 Catania, Italy
Viviana Triaca
Medicina Molecolare e Traslazionale “Rita Levi Montalcini”, Institute of Cellular Biology and Neurobiology (IBCN), National Research Council (CNR), c/o Policlinico Umberto I, University of Rome “La Sapienza”, Via del Policlinico 255, 00161 Rome, Italy
Giuseppina Amadoro
Institute of Translational Pharmacology (IFT), National Research Council (CNR), 00131 Rome, Italy
Valentina Latina
European Brain Research Institute, Viale Regina Elena 295, 00161, 64-65, 00143 Rome, Italy
Pietro Calissano
European Brain Research Institute, Viale Regina Elena 295, 00161, 64-65, 00143 Rome, Italy
Alessio Travaglia
Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Vincenzo Giuseppe Nicoletti
Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy
Diego La Mendola
Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy
Enrico Rizzarelli
Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Nerve growth factor (NGF) is a protein necessary for development and maintenance of the sympathetic and sensory nervous systems. We have previously shown that the NGF N-terminus peptide NGF(1-14) is sufficient to activate TrkA signaling pathways essential for neuronal survival and to induce an increase in brain-derived neurotrophic factor (BDNF) expression. Cu2+ ions played a critical role in the modulation of the biological activity of NGF(1-14). Using computational, spectroscopic, and biochemical techniques, here we report on the ability of a newly synthesized peptide named d-NGF(1-15), which is the dimeric form of NGF(1-14), to interact with TrkA. We found that d-NGF(1-15) interacts with the TrkA-D5 domain and induces the activation of its signaling pathways. Copper binding to d-NGF(1-15) stabilizes the secondary structure of the peptides, suggesting a strengthening of the noncovalent interactions that allow for the molecular recognition of D5 domain of TrkA and the activation of the signaling pathways. Intriguingly, the signaling cascade induced by the NGF peptides ultimately involves cAMP response element-binding protein (CREB) activation and an increase in BDNF protein level, in keeping with our previous result showing an increase of BDNF mRNA. All these promising connections can pave the way for developing interesting novel drugs for neurodegenerative diseases.
