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Open AccessArticle

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

1
Institute of Biochemistry and Cell Biology, National Research Council (CNR-IBBC), International Campus A. Buzzati Traverso, Via E. Ramarini 32, Monterotondo, Rome 00015, Italy
2
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
3
European Brain Research Institute (EBRI Foundation), Viale Regina Elena 295, Rome 00161, Italy
4
IRCCS S. Lucia Foundation, Via del Fosso di Fiorano 64, Rome 00143, Italy
5
Department of Systems Medicine, University of Rome “TorVergata”, Via Montpellier 1, Rome 00133, Italy
6
Department of Pharmacy, University of Pisa, via Bonanno Pisano 6, Pisa 56126, Italy
7
Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
8
Institute of Crystallography, National Research Council (CNR-IC), Via Paolo Gaifami 18, Catania 95126, Italy
*
Author to whom correspondence should be addressed.
These authors contribute equally to this paper.
Biomolecules 2020, 10(2), 216; https://doi.org/10.3390/biom10020216
Received: 23 December 2019 / Revised: 22 January 2020 / Accepted: 26 January 2020 / Published: 1 February 2020
(This article belongs to the Special Issue New Targets and Strategies in Regenerative Medicine)
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.
Keywords: NGF mimetic; hNGF1–14; TrkA agonist; cholinergic neurons; DRG; neurotrophic therapy NGF mimetic; hNGF1–14; TrkA agonist; cholinergic neurons; DRG; neurotrophic therapy
MDPI and ACS Style

Triaca, V.; Fico, E.; Sposato, V.; Caioli, S.; Ciotti, M.T.; Zona, C.; Mercanti, D.; La Mendola, D.; Satriano, C.; Rizzarelli, E.; Tirassa, P.; Calissano, P. hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay. Biomolecules 2020, 10, 216.

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