hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay.

Autor: Triaca V; Institute of Biochemistry and Cell Biology, National Research Council (CNR-IBBC), International Campus A. Buzzati Traverso, Via E. Ramarini 32, Monterotondo, Rome 00015, Italy., Fico E; Institute of Biochemistry and Cell Biology, National Research Council (CNR-IBBC), at Department of Sense Organs, University of Rome ' La Sapienza', Viale del Policlinico 155, Rome 00161, Italy., Sposato V; European Brain Research Institute (EBRI Foundation), Viale Regina Elena 295, Rome 00161, Italy., Caioli S; IRCCS S. Lucia Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy., Ciotti MT; Institute of Biochemistry and Cell Biology, National Research Council (CNR-IBBC), at Department of Sense Organs, University of Rome ' La Sapienza', Viale del Policlinico 155, Rome 00161, Italy., Zona C; IRCCS S. Lucia Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy.; Department of Systems Medicine, University of Rome 'TorVergata', Via Montpellier 1, Rome 00133, Italy., Mercanti D; Institute of Biochemistry and Cell Biology, National Research Council (CNR-IBBC), at Department of Sense Organs, University of Rome ' La Sapienza', Viale del Policlinico 155, Rome 00161, Italy., La Mendola D; Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, Pisa 56126, Italy., Satriano C; Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy., Rizzarelli E; Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy.; Institute of Crystallography, National Research Council (CNR-IC), Via Paolo Gaifami 18, Catania 95126, Italy., Tirassa P; Institute of Biochemistry and Cell Biology, National Research Council (CNR-IBBC), at Department of Sense Organs, University of Rome ' La Sapienza', Viale del Policlinico 155, Rome 00161, Italy., Calissano P; European Brain Research Institute (EBRI Foundation), Viale Regina Elena 295, Rome 00161, Italy.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2020 Feb 01; Vol. 10 (2). Date of Electronic Publication: 2020 Feb 01.
DOI: 10.3390/biom10020216
Abstrakt: In the last decade, Nerve Growth Factor (NGF)-based clinical approaches have lacked specific and efficient Tyrosine Kinase A (TrkA) agonists for brain delivery. Nowadays, the characterization of novel small peptidomimetic is taking centre stage in preclinical studies, in order to overcome the main size-related limitation in brain delivery of NGF holoprotein for Central Nervous System (CNS) pathologies. Here we investigated the NGF mimetic properties of the human NGF 1-14 sequence (hNGF1-14) and its derivatives, by resorting to primary cholinergic and dorsal root ganglia (DRG) neurons. Briefly, we observed that: 1) hNGF1-14 peptides engage the NGF pathway through TrkA phosphorylation at tyrosine 490 (Y490), and activation of ShcC/PI3K and Plc-γ/MAPK signalling, promoting AKT-dependent survival and CREB-driven neuronal activity, as seen by levels of the immediate early gene c-Fos, of the cholinergic marker Choline Acetyltransferase (ChAT), and of Brain Derived Neurotrophic Factor (BDNF); 2) their NGF mimetic activity is lost upon selective TrkA inhibition by means of GW441756; 3) hNGF1-14 peptides are able to sustain DRG survival and differentiation in absence of NGF. Furthermore, the acetylated derivative Ac-hNGF1-14 demonstrated an optimal NGF mimetic activity in both neuronal paradigms and an electrophysiological profile similar to NGF in cholinergic neurons. Cumulatively, the findings here reported pinpoint the hNGF1-14 peptide, and in particular its acetylated derivative, as novel, specific and low molecular weight TrkA specific agonists in both CNS and PNS primary neurons.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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