The Native Copper- and Zinc- Binding Protein Metallothionein Blocks Copper-Mediated Aβ Aggregation and Toxicity in Rat Cortical Neurons

Chung, Roger S.; Howells, Claire; Eaton, Emma D.; Shabala, Lana; Zovo, Kairit; Palumaa, Peep; Sillard, Rannar; Woodhouse, Adele; Bennett, Bill; Ray, Shannon; Vickers, James C.; West, Adrian K.

doi:10.1371/journal.pone.0012030

Cited by 61 publications

(48 citation statements)

References 47 publications

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“…MTs bind copper with high affinity, suggesting a role in copper homeostasis (Chung et al, 2008, 2010), and mice displaying copper overload crossed with an MT 1/2 knockout did not survive past infancy (Kelly and Palmiter, 1996). Exchange between protein and metal has been observed in studies that found MTs prevented copper-induced aggregation of amyloid beta peptide or alpha-synuclein (Meloni et al, 2008; Meloni and Vašák, 2011; De Ricco et al, 2015b).…”

Section: Metallothioneinsmentioning

confidence: 99%

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

et al. 2017

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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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Section: Metallothioneinsmentioning

confidence: 99%

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

et al. 2017

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“…This provides an estimated average Cu I affinity for MT‐2A of 2.4×10 15 m −1 and positive cooperativity with a Hill coefficient of ≈4 (the value for Mt Csp1 is around 3) . A very similar average Cu I affinity has been measured for MT‐3 (2.1×10 15 m −1 ), but in this case Cu I binding shows only weak positive cooperativity (Hill coefficient of 1.3) . These Cu I affinity measurements only considered the 1:1 Cu I :DTT complex, as previously discussed, resulting in values being underestimated by as much as 3–4 orders of magnitude.…”

Section: Bacterial Copper Storage Proteinsmentioning

confidence: 99%

The Coordination Chemistry of Copper Uptake and Storage for Methane Oxidation

Dennison

2018

Chemistry A European J

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Methanotrophs are remarkable bacteria that utilise large quantities of copper (Cu) to oxidize the potent greenhouse gas methane. To assist in providing the Cu they require for this process some methanotrophs can secrete the Cu‐sequestering modified peptide methanobactin. These small molecules bind CuI with very high affinity and crystal structures have given insight into why this is the case, and also how the metal ion may be released within the cell. A much greater proportion of methanotrophs, genomes of which have been sequenced, possess a member of a newly discovered bacterial family of copper storage proteins (the Csps). These are tetramers of four‐helix bundles whose cores are lined with Cys residues enabling the binding of large numbers of CuI ions. In methanotrophs, a Csp exported from the cytosol stores CuI for the active site of the ubiquitous enzyme that catalyses the oxidation of methane. The presence of cytosolic Csps, not only in methanotrophs but in a wide range of bacteria, challenges the dogma that these organisms have no requirement for Cu in this location. The properties of the Csps, with an emphasis on CuI binding and the structures of the sites formed, are the primary focus of this review.

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“…Furthermore, it is able to influence the response of both neurons and glial cells, and it may also have an effect on immune system cells. For example, MT promotes regenerative neuronal growth after injury (Chung et al 2003) and separately, it improves neuronal survival in the face of a variety of neurotoxic insults (Ambjorn et al 2008) – for example, following Aβ administration (Chung et al 2010). MT appears to do this by stimulating receptors of the lipoprotein receptor-related protein (LRP) family and triggering a pathway involving Erk1 and CREB activation (Ambjorn et al 2008).…”

Section: Endogenous Neuroprotective Molecules (Akw Gjg)mentioning

confidence: 99%

New Strategies in Neuroprotection and Neurorepair

et al. 2011

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There are currently few clinical strategies in place, which provide effective neuroprotection and repair, despite an intense international effort over the past decades. One possible explanation for this is that a deeper understanding is required of how endogenous mechanisms act to confer neuroprotection. This mini-review reports the proceedings of a recent workshop “Neuroprotection and Neurorepair: New Strategies” (Iguazu Falls, Misiones, Argentina, April 11–13, 2011, Satellite Symposium of the V Neurotoxicity Society Meeting, 2011) in which four areas of active research were identified to have the potential to generate new insights into this field. Topics discussed were i) metallothionein and other multipotent neuroprotective molecules; ii) oxidative stress and their signal mediated pathways in neuroregeneration; iii) neurotoxins in glial cells, and iv) drugs of abuse with neuroprotective effects.

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The Native Copper- and Zinc- Binding Protein Metallothionein Blocks Copper-Mediated Aβ Aggregation and Toxicity in Rat Cortical Neurons

Cited by 61 publications

References 47 publications

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

The Coordination Chemistry of Copper Uptake and Storage for Methane Oxidation

New Strategies in Neuroprotection and Neurorepair

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