Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Abstract

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer's disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu(2+) homeostasis is a prominent factor in the development of neurological pathologies. The N-terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu(2+) ions has been reported up to now. Cu(2+) complexes of the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of N-terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT-geometry optimizations. Coordination features of the acetylated form, Ac-BDNF(1-12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1-12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu(2+) coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1-12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu(2+) may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…The production and maturation of BDNF in the brain is regulated by Cu 2+ -dependent metalloproteinases. In SHSY5Y cells, Cu 2+ treatment decreased pro-BDNF level in cells and increased pro-and mature BDNF levels in the medium [128] with a strong decrease of the proliferative activity of both cleaved BDNF (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and the full length protein [129]. Application of zinc chelator induced reduction of BDNF level, synaptic plasticity-related proteins and dendritic spine density in vivo, which further confirm that appropriate amount of Zn 2+ is essential in brain development and the synaptic functions [130].…”

Association Study of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor Gene with Clozapine-Induced Metabolic Syndrome: Preliminary Results

“…Altered BDNF signaling has been shown to involved in a variety of peripheral and central nervous system disorders, including dementia, amyotrophic lateral sclerosis, depression and schizophrenia, etc [32]. A recent study implicated BDNF in the control of GLU, lipid and antioxidant metabolism [33], which is considered an anorexigenic signal in the central control of food intake [34].…”

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 method of Daura and Van Gunsteren (Daura et al, 1999) was used in post-processing phase to cluster the resulting trajectories, with a cutoff of 3 Å calculated on the backbone atoms as implemented in the clustering utility provided in the GROMACS package (Hess, 2008). This simulation protocol has successfully been tested in predicting the conformational features of small peptides (Travaglia et al, 2012a, 2013a; Pietropaolo et al, 2015), combined with unbiased simulations for disclosing the structural packing enhanced by specific residues (Pietropaolo et al, 2007, 2008). …”