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

Viviana Triaca, Elena Fico, Valentina Sposato, Silvia Caioli, Maria Teresa Ciotti, Cristina Zona, Delio Mercanti, Diego La Mendola, Cristina Satriano, Enrico Rizzarelli, Paola Tirassa, Pietro Calissano

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalBiomolecules
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

Keywords

  • cholinergic neurons
  • DRG
  • hNGF1–14
  • neurotrophic therapy
  • NGF mimetic
  • TrkA agonist

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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