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Copper and Neurodegenerative Diseases
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Copper and Neurodegenerative Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 9185

Special Issue Editor

Prof. Dr. Michele Maffia

E-Mail Website
Guest Editor
Department of Biological and Environmental Science and Technology, University of Salento, 73100 Lecce, Italy
Interests: cell physiology and differentiation; adaptive physiology; neurodegeneration; cancer biology; functional proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Copper is one of the most important biometals in the organism, thanks to its ability to shift from cuprous to cupric state and vice versa, acting as a catalyst for many enzymatic reactions, such as respiration, free radical detoxification, and neurotransmission. On the other hand, its redox potential can catalyze free radical formation, causing DNA integrity alteration and lipid peroxidation.

Copper dysmetabolism is a common feature of many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), whose incidence increases with the ageing population. These are incurable diseases, evolving in a progressive degeneration and death of neuronal cells.

Patients with neurodegenerative disorders show changes in the overall copper levels in the brain, or alterations of its relative distribution between different functional regions; this results in protein aggregation, alterations in protein degradation pathways, oxidative stress, inflammation, and mitochondrial dysfunction.

The correlation between alterations of brain copper homeostasis and copper-mediated cell death pathways suggests that the modulation of metal levels could be a target for developing more effective therapies for neurodegenerative disorders.

This Special Issue "Copper and Neurodegenerative Diseases” encourages original research papers that expand existing perspectives and clarify the copper-based mechanisms underlying neurodegeneration.

Review articles covering the most recent discoveries in this area and new therapeutic approaches targeting copper dyshomeostasis are also welcome.

Prof. Dr. Michele Maffia
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegeneration
  • neurodegenerative diseases
  • neuronal differentiation
  • copper homeostasis
  • copper dyshomeostasis
  • copper transport
  • copper-binding proteins
  • oxidative stress
  • inflammation
  • protein aggregation
  • protein degradation pathways

Published Papers (3 papers)

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Research

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14 pages, 5472 KiB  
Article
Oxidase Reactivity of CuII Bound to N-Truncated Aβ Peptides Promoted by Dopamine
by Chiara Bacchella, Simone Dell’Acqua, Stefania Nicolis, Enrico Monzani and Luigi Casella
Int. J. Mol. Sci. 2021, 22(10), 5190; https://doi.org/10.3390/ijms22105190 - 14 May 2021
Cited by 3 | Viewed by 1795
Abstract
The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-β peptides and by the stability of the resulting complexes. Amino-terminal copper and nickel binding motifs (ATCUN) identified in truncated Aβ sequences starting with Phe4 show very high affinity for copper(II) [...] Read more.
The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-β peptides and by the stability of the resulting complexes. Amino-terminal copper and nickel binding motifs (ATCUN) identified in truncated Aβ sequences starting with Phe4 show very high affinity for copper(II) ions. Herein, we study the oxidase activity of [Cu–Aβ4−x] and [Cu–Aβ1−x] complexes toward dopamine and other catechols. The results show that the CuII–ATCUN site is not redox-inert; the reduction of the metal is induced by coordination of catechol to the metal and occurs through an inner sphere reaction. The generation of a ternary [CuII–Aβ–catechol] species determines the efficiency of the oxidation, although the reaction rate is ruled by reoxidation of the CuI complex. In addition to the N-terminal coordination site, the two vicinal histidines, His13 and His14, provide a second Cu-binding motif. Catechol oxidation studies together with structural insight from the mixed dinuclear complexes Ni/Cu–Aβ4−x reveal that the His-tandem is able to bind CuII ions independently of the ATCUN site, but the N-terminal metal complexation reduces the conformational mobility of the peptide chain, preventing the binding and oxidative reactivity toward catechol of CuII bound to the secondary site. Full article
(This article belongs to the Special Issue Copper and Neurodegenerative Diseases)
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18 pages, 6420 KiB  
Article
Copper Dependent Modulation of α-Synuclein Phosphorylation in Differentiated SHSY5Y Neuroblastoma Cells
by Marco Greco, Chiara Carmela Spinelli, Lidia De Riccardis, Alessandro Buccolieri, Simona Di Giulio, Debora Musarò, Claudia Pagano, Daniela Manno and Michele Maffia
Int. J. Mol. Sci. 2021, 22(4), 2038; https://doi.org/10.3390/ijms22042038 - 18 Feb 2021
Cited by 8 | Viewed by 3211
Abstract
Copper (Cu) dyshomeostasis plays a pivotal role in several neuropathologies, such as Parkinson’s disease (PD). Metal accumulation in the central nervous system (CNS) could result in loss-of-function of proteins involved in Cu metabolism and redox cycling, generating reactive oxygen species (ROS). Moreover, neurodegenerative [...] Read more.
Copper (Cu) dyshomeostasis plays a pivotal role in several neuropathologies, such as Parkinson’s disease (PD). Metal accumulation in the central nervous system (CNS) could result in loss-of-function of proteins involved in Cu metabolism and redox cycling, generating reactive oxygen species (ROS). Moreover, neurodegenerative disorders imply the presence of an excess of misfolded proteins known to lead to neuronal damage. In PD, Cu accumulates in the brain, binds α-synuclein, and initiates its aggregation. We assessed the correlation between neuronal differentiation, Cu homeostasis regulation, and α-synuclein phosphorylation. At this purpose, we used differentiated SHSY5Y neuroblastoma cells to reproduce some of the characteristics of the dopaminergic neurons. Here, we reported that differentiated cells expressed a significantly higher amount of a copper transporter protein 1 (CTR1), increasing the copper uptake. Cells also showed a significantly more phosphorylated form of α-synuclein, further increased by copper treatment, without modifications in α-synuclein levels. This effect depended on the upregulation of the polo-like kinase 2 (PLK2), whereas the levels of the relative protein phosphatase 2A (PP2A) remained unvaried. No changes in the oxidative state of the cells were identified. The Cu dependent alteration of α-synuclein phosphorylation pattern might potentially offer new opportunities for clinical intervention. Full article
(This article belongs to the Special Issue Copper and Neurodegenerative Diseases)
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Review

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25 pages, 1096 KiB  
Review
Subcellular Localization of Copper—Cellular Bioimaging with Focus on Neurological Disorders
by Barbara Witt, Dirk Schaumlöffel and Tanja Schwerdtle
Int. J. Mol. Sci. 2020, 21(7), 2341; https://doi.org/10.3390/ijms21072341 - 28 Mar 2020
Cited by 33 | Viewed by 3641
Abstract
As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer’s disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus [...] Read more.
As an essential trace element, copper plays a pivotal role in physiological body functions. In fact, dysregulated copper homeostasis has been clearly linked to neurological disorders including Wilson and Alzheimer’s disease. Such neurodegenerative diseases are associated with progressive loss of neurons and thus impaired brain functions. However, the underlying mechanisms are not fully understood. Characterization of the element species and their subcellular localization is of great importance to uncover cellular mechanisms. Recent research activities focus on the question of how copper contributes to the pathological findings. Cellular bioimaging of copper is an essential key to accomplish this objective. Besides information on the spatial distribution and chemical properties of copper, other essential trace elements can be localized in parallel. Highly sensitive and high spatial resolution techniques such as LA-ICP-MS, TEM-EDS, S-XRF and NanoSIMS are required for elemental mapping on subcellular level. This review summarizes state-of-the-art techniques in the field of bioimaging. Their strengths and limitations will be discussed with particular focus on potential applications for the elucidation of copper-related diseases. Based on such investigations, further information on cellular processes and mechanisms can be derived under physiological and pathological conditions. Bioimaging studies might enable the clarification of the role of copper in the context of neurodegenerative diseases and provide an important basis to develop therapeutic strategies for reduction or even prevention of copper-related disorders and their pathological consequences. Full article
(This article belongs to the Special Issue Copper and Neurodegenerative Diseases)
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