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  • Metallothionein, copper and alpha-synuclein in alpha-synucleinopathies

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    Author(s)
    Okita, Yuho
    Rcom-H'cheo-Gauthier, Alexandre N
    Goulding, Michael
    Chung, Roger S
    Faller, Peter
    Pountney, Dean L
    Griffith University Author(s)
    Pountney, Dean L.
    Goulding, Michael A.
    Rcom-H'cheo-Gauthier, Alexandre N.
    Okita, Yuho
    Year published
    2017
    Metadata
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    Abstract
    Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies. In PD, total tissue copper is decreased, ...
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    Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies. In PD, total tissue copper is decreased, including neuromelanin-bound copper and there is a reduction in copper transporter CTR-1. Conversely cerebrospinal fluid (CSF) copper is increased. MT-1/2 expression is increased in activated astrocytes in alpha-synucleinopathies, yet expression of the neuronal MT-3 isoform may be reduced. MTs have been implicated in inflammatory states to perform one-way exchange of copper, releasing free zinc and recent studies have found copper bound to alpha-synuclein is transferred to the MT-3 isoform in vitro and MT-3 is found bound to pathological alpha-synuclein aggregates in the alpha-synucleinopathy, multiple systems atrophy. Moreover, both MT and alpha-synuclein can be released and taken up by neural cells via specific receptors and so may interact both intra- and extra-cellularly. Here, we critically review the role of MTs in copper dyshomeostasis and alpha-synuclein aggregation, and their potential as biomarkers and therapeutic targets.
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    Journal Title
    Frontiers in Neuroscience
    Volume
    11
    DOI
    https://doi.org/10.3389/fnins.2017.00114
    Copyright Statement
    © 2017 Okita, Rcom-H'cheo-Gauthier, Goulding, Chung, Faller and Pountney. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
    Subject
    Neurosciences not elsewhere classified
    Neurosciences
    Psychology
    Cognitive Sciences
    Publication URI
    http://hdl.handle.net/10072/343111
    Collection
    • Journal articles

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