A small linear peptide encompassing the NGF N-terminus partly mimics the biological activities of the entire neurotrophin in PC12 cells.
Ever since the discovery of its neurite growth promoting activity in sympathetic and sensory ganglia, nerve growth factor (NGF) became the prototype of the large family of neurotrophins. The use of primary cultures and clonal cell lines has revealed several distinct actions of NGF and other neurotrophins. Among several models of NGF activity, the clonal cell line PC12 is the most widely employed. Thus, in the presence of NGF, through the activation of the transmembrane protein TrkA, these cells undergo a progressive mitotic arrest and start to grow electrically excitable neuritis. A vast number of studies opened intriguing aspects of NGF mechanisms of action, its biological properties, and potential use as therapeutic agents. In this context, identifying and utilizing small portions of NGF is of great interest and involves several human diseases including Alzheimer's disease. Here we report the specific action of the peptide encompassing the 1-14 sequence of the human NGF (NGF(1-14)), identified on the basis of scattered indications present in literature. The biological activity of NGF(1-14) was tested on PC12 cells, and its binding with TrkA was predicted by means of a computational approach. NGF(1-14) does not elicit the neurite outgrowth promoting activity, typical of the whole protein, and it only has a moderate action on PC12 proliferation. However, this peptide exerts, in a dose and time dependent fashion, an effective and specific NGF-like action on some highly conserved and biologically crucial intermediates of its intracellular targets such as Akt and CREB. These findings indicate that not all TrkA pathways must be at all times operative, and open the possibility of testing each of them in relation with specific NGF needs, biological actions, and potential therapeutic use.
†Center for Neural Science, New York University, 4 Washington Place, New York, New York 10003, United States.
Alessio
A
Travaglia
‡Dipartimento di Scienze della Salute, Università di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.
Adriana
A
Pietropaolo
§Istituto di Bioimmagini e Fisiologia Molecolare (IBFM)-CNR, C.da Pietrapollastra-Pisciotto, Cefalù, Palermo 90015, Italy.
Rossana
R
Di Martino
∥Dipartimento di Scienze Biomediche e Biotecnologiche - Sezione di Biochimica Medica, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy.|⊥Istituto Nazionale Biostrutture e Biosistemi (INBB) - Sezione Biomolecole, Consorzio Interuniversitario, Viale Medaglie d'Oro 305, 00136 Roma, Italy.
Vincenzo G
VG
Nicoletti
#Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
Diego
D
La Mendola
∇European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64-65, 00143 Rome, Italy.
Pietro
P
Calissano
○IBB-CNR, UOS Catania, via Paolo Gaifami 18, 95126 Catania, Italy.
Enrico
E
Rizzarelli
D000818:Animals; D049108:Cell Enlargement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D062105:Molecular Docking Simulation; D020932:Nerve Growth Factor / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D020932:Nerve Growth Factor; D020917:Receptor, trkA
CREB; ERK; PC12; Peptidomimetic; nerve growth factor; neuroprotection