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Issue Date: 26-Feb-2013
Authors: Travaglia, Alessio
Title: Memory, metals and neurotrophins
Abstract: In the last decades, one of the main interests of neuroscientists has been to unravel the molecular mechanisms of memory. Neurotrophins are proteins involved in development and survival of neurons as well as they are active player in memory formation and synaptic plasticity. d-block biometals, especially copper and zinc, are emerging as crucial player in the physiology of the brain. As matter of fact, there is a significant overlap between brain areas in which the highest concentration of metals have been measured and those where the neurotrophins exert their biological activity. Metal ions can directly modulate their activities, through conformational changes, and/or indirectly by activating their downstream signaling in a neurotrophin-independent mode. Despite the importance of these modulations, there is the lack of experimental data regarding the coordination features of metal ions complexes with neurotrophins. The N-terminal domain of neurotrophins is critical for the binding selectivity and activation of their receptors. We synthesized the N-terminus peptide fragments encompassing the human neurotrophins, characterized their copper(II) and zinc(II) complexes by means of potentiometric, spectroscopic (UV/Vis, CD, NMR and EPR) techniques and DFT calculations, tested the metal-driven biological effect. The coordination features of acetylated as well as single point mutated peptides have been also studied to prove the involvement of each donor group. The functional interaction of biometals with neurotrophins and related peptides has been tested by biological assay on SHSY5Y neuroblastoma cell, providing evidence of the correlation between biological activity and coordination environment. Our biochemical characterizations of the neurotrophins signaling, both in vitro and in vivo, have shed some light on the possible use of neurotrophins and neurotrophins-like peptides in neurological disorders. Indeed, the use of neurotrophins in the early stages of neurodegenerative diseases has recently gained attention. However, there are limits to such therapy, e.g. insufficient permeability of the blood-brain barrier and inappropriate activation of receptors that trigger side effects. The use of peptidomimetic combined with systems that guarantee their delivery might allow to overcome these restrictions. In view of application as functional nanoplatforms for smart drug delivery, supported lipid bilayers formed by neurotrophin peptidomimetics/small unilamellar vescicles adsorption on silica (both planar model and nanoparticles) have been characterized. In conclusion, the interaction of metals and neurotrophins might represent a crossroad for neuronal physiology. Better understanding of metal ion-driven neurotrophins signal transduction and intercellular signaling, as well as vice versa, the role of neurotrophins in the control of metal ions homeostasis, could disclose helpful information and it is therefore strongly raising as one of the most critical step in the study of neurodegenerative diseases as well in the physiological mechanisms of memory.
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