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Review
. 2017 Apr 4:11:114.
doi: 10.3389/fnins.2017.00114. eCollection 2017.

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

Yuho Okita  1 , Alexandre N Rcom-H'cheo-Gauthier  1 , Michael Goulding  1 , Roger S Chung  2 , Peter Faller  3   4 , Dean L Pountney  1
Affiliations
Review

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

Yuho Okita et al. Front Neurosci. .

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, 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.

Keywords: Parkinson's disease; copper; dementia with lewy bodies; metallothionein; multiple system atrophy; α-synuclein.

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Figures

Figure 1
Figure 1
(A) Sequence alignment showing alpha-synuclein copper binding ligands overlap with PD-linked H50 mutation in membrane binding domain. Red represents the known point mutations in familial Parkinson's disease in alpha-synuclein. Yellow represents the KTK repeats in the N-terminus which are involved in lipid interaction. (B) Immunofluorescence shows MT-3 co-localizes with alpha-synuclein in glial cytoplasmic inclusions in MSA brain tissue. (C) MT-3 associates with alpha-synuclein filaments in isolated alpha-synuclein inclusions by immunogold-labeling (black dots; arrows) (Pountney et al., 2011).
Figure 2
Figure 2
Schematic representation of copper, MT, α-syn interactions in PD. MT-1/2 expression is primarily astrocytic in the brain, whereas MT-3 is neuronal. MTs and alpha-synuclein may interact either intra- or extracellularly, either directly or indirectly. Copper induces alpha-synuclein aggregation, whereas MT's chelate copper. Copper binding to alpha-synuclein generates ROS, whereas MTs are powerful anti-oxidants.
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