The inorganic perspectives of neurotrophins and Alzheimer's disease

Travaglia, Alessio; Pietropaolo, Adriana; Mendola, Diego La; Nicoletti, Vincenzo Giuseppe; Rizzarelli, Enrico

doi:10.1016/j.jinorgbio.2011.10.017

Cited by 30 publications

(54 citation statements)

References 140 publications

(179 reference statements)

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“…Metal ions, especially copper and zinc, are known to affect the NGF activity (Hwang et al, 2007; Travaglia et al, 2012b). Copper may be required for various aspects of NGF-stimulated neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the proliferative effect of NGF(1–14) significantly increased in the presence of Zn 2+ or Cu 2+ , whereas the activity of Ac-NGF(1–14) resulted practically unaffected under the same experimental conditions. Furthermore, while SHSY5Y cell culture treated with NGF and copper showed a synergic increase in the cell number, on the contrary, co-treatment with zinc and murine NGF inhibited the cell growth (Travaglia et al, 2011, 2012b). …”

Section: Introductionmentioning

confidence: 99%

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The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Pandini

Satriano

Pietropaolo³

et al. 2016

Front. Neurosci.

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The nerve growth factor (NGF) N-terminus peptide, NGF(1–14), and its acetylated form, Ac-NGF(1–14), were investigated to scrutinize the ability of this neurotrophin domain to mimic the whole protein. Theoretical calculations demonstrated that non-covalent forces assist the molecular recognition of TrkA receptor by both peptides. Combined parallel tempering/docking simulations discriminated the effect of the N-terminal acetylation on the recognition of NGF(1–14) by the domain 5 of TrkA (TrkA-D5). Experimental findings demonstrated that both NGF(1–14) and Ac-NGF(1–14) activate TrkA signaling pathways essential for neuronal survival. The NGF-induced TrkA internalization was slightly inhibited in the presence of Cu2+ and Zn2+ ions, whereas the metal ions elicited the NGF(1–14)-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF(1–14)-induced receptor internalization. The crucial role of the metals was confirmed by experiments with the metal-chelator bathocuproine disulfonic acid, which showed different inhibitory effects in the signaling cascade, due to different metal affinity of NGF, NGF(1–14) and Ac-NGF(1–14). The NGF signaling cascade, activated by the two peptides, induced CREB phosphorylation, but the copper addition further stimulated the Akt, ERK and CREB phosphorylation in the presence of NGF and NGF(1–14) only. A dynamic and quick influx of both peptides into PC12 cells was tracked by live cell imaging with confocal microscopy. A significant role of copper ions was found in the modulation of peptide sub-cellular localization, especially at the nuclear level. Furthermore, a strong copper ionophoric ability of NGF(1–14) was measured. The Ac-NGF(1–14) peptide, which binds copper ions with a lower stability constant than NGF(1–14), exhibited a lower nuclear localization with respect to the total cellular uptake. These findings were correlated to the metal-induced increase of CREB and BDNF expression caused by NGF(1–14) stimulation. In summary, we here validated NGF(1–14) and Ac-NGF(1–14) as first examples of monomer and linear peptides able to activate the NGF-TrkA signaling cascade. Metal ions modulated the activity of both NGF protein and the NGF-mimicking peptides. Such findings demonstrated that NGF(1–14) sequence can reproduce the signal transduction of whole protein, therefore representing a very promising drug candidate for further pre-clinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Pandini

Satriano

Pietropaolo³

et al. 2016

Front. Neurosci.

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“…The formation of mixed metal Cu(II)-Ni(II) heterodinuclear complexes has also been described in which Cu(II) ions are coordinated to the amino terminus, while Ni(II) occupies the internal His sites. 206 The ultimate goal of these studies is to find the appropriate treatment of AD and the involvement of metal complexes and chelating agents in these studies was also surveyed. The governing role of His and Pro residues in complex formation was concluded in this study, too.…”

Section: Thermodynamic Kinetic and Structural Studies On The Metal Cmentioning

confidence: 99%

Metal complexes of amino acids and peptides

Farkas¹,

Sóvágó²

2014

Amino Acids, Peptides and Proteins

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“…Metabolic dysfunction of NGF is involved in Alzheimer’s Diseases (AD) occurrence [9,10,11]. Metal ions play a role in AD [12,13,14] and copper and zinc ions can modulate NGF activity in the same brain areas affected by metal dyshomeostasis in pathological conditions [15,16,17]. Metal binding can induce NGF conformational changes that hinder the recognition process with its cellular receptors [18,19,20].…”

Section: Introductionmentioning

confidence: 99%

Copper Binding Features of Tropomyosin-Receptor-Kinase-A Fragment: Clue for Neurotrophic Factors and Metals Link

Magrı̀

Mendola

2018

IJMS

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The nerve growth factor (NGF) is a neurotrophin essential for the development and maintenance of neurons, whose activity is influenced by copper ions. The NGF protein exerts its action by binding to its specific receptor, TrkA. In this study, a specific domain of the TrkA receptor, region 58–64, was synthesized and its copper(II) complexes characterized by means of potentiometric and spectroscopic studies. The two vicinal histidine residues provide excellent metal anchoring sites and, at physiological pH, a complex with the involvement of the peptide backbone amide nitrogen is the predominant species. The TrkA peptide is competitive for metal binding with analogous peptides due to the N-terminal domain of NGF. These data provide cues for future exploration of the effect of metal ions on the activity of the NGF and its specific cellular receptor.

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The inorganic perspectives of neurotrophins and Alzheimer's disease

Cited by 30 publications

References 140 publications

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Metal complexes of amino acids and peptides

Copper Binding Features of Tropomyosin-Receptor-Kinase-A Fragment: Clue for Neurotrophic Factors and Metals Link

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