Copper‐dependent regulation of NMDA receptors by cellular prion protein: implications for neurodegenerative disorders

Stys, Peter K.; You, Haitao; Zamponi, Gerald W.

doi:10.1113/jphysiol.2011.225276

Cited by 100 publications

(86 citation statements)

References 135 publications

(148 reference statements)

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“…An important mechanism for toxicity in the copper overloadi st he capability of free or loosely bound cooper to catalyset he productionofr eactive oxygen species (ROS). [1,2] Mismetabolism of copperh as been reported in several neurodegenerative diseases, such as Alzheimer's disease (AD), [3] Parkinson'sd isease (PD), [4][5][6] prion disease, [7,8] and amyotrophic lateral sclerosis. [9,10] Often Cu is found to be bound to ad isease-specific amyloidogenic peptide or protein.…”

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confidence: 99%

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

et al. 2015

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Copper binding to α-synuclein (aS) and to amyloid-β (Ab) has been connected to Parkinson's and Alzheimer's disease (AD), respectively, because Cu ions can modulate the peptide aggregation, and these Cu ⋅ peptide complexes can catalyse the production of reactive oxygen species (ROS). In a significant proportion of AD brains, aggregation of aS and Ab has been detected, and it was proposed that Ab and aS interact with each other. Thus, we investigated the potential interactions of Ab and aS through their binding of copper(I) and copper(II). Additionally, β-synuclein (bS) was investigated, due to its additional methionine residue, a potential Cu(I) ligand. We found that: 1) the peptides containing the Cu-binding domains Ab1-16, aS1-15 and bS1-15 have similar affinities towards Cu(II) and towards Cu(I), with Ab1-16 being slightly stronger, 2) in the case of Cu(I), the additional Met residue in bS1-15 increased the affinity slightly, 3) the exchange of Cu(I/II) between the two peptides is rapid (≤ ms), 4) a/bS1-15 and Ab1-16 form a heterodimeric complex with Cu(II), 5) Cu(I) probably promotes a transient ternary complex, 6) the different Cu(I/II) coordination of Ab1-16, aS1-15 and bS1-15 impacts the capacity to produce ROS and to oxidise catechol, and 7) when Ab1-16, aS1-15 and Cu are present, the ROS production more closely resembles that by Ab1-16. The work gives insights into the coordination chemistry of these related peptides, and the relevance of coordination differences, the ternary complex and ROS production are discussed.

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confidence: 99%

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

et al. 2015

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“…Indeed, PrP-deficient neurons exhibit a lower glutathione activity and susceptibility to hydrogen peroxide [23]. Recent studies suggest that PrP C regulates the excitability of NMDA-type glutamate receptor in a Cu-dependent manner [24]. Moreover, Cu 2+ influences the gene expression and cellular trafficking of PrP [25].…”

Section: Cu and Normal Prion Proteinmentioning

confidence: 99%

“…APP is localized to the presynaptic region of synapses and AβP is secreted into synaptic clefts in the presence of neuronal stimuli [79]. Meanwhile, PrP C is localized to the postsynaptic membrane and is coupled to glutamate receptors [24]. Both of PrP C and APP are metal-binding proteins and regulate metal homeostasis.…”

Section: Protective Substances Against Prp106-126-induced Neurotoxicitymentioning

confidence: 99%

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

Kawahara¹,

Tanaka²,

Mizuno³

2017

Prion - An Overview

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Prion diseases are progressive neurodegenerative diseases that are associated with the conformational conversion of normal cellular prion protein (PrP C ) into abnormal pathogenic prion protein (PrP Sc ). PrP C is a metal-binding protein that is located in the synapse and possesses the ability to bind to various metals, including Cu, Zn, Mn and Fe. Moreover, increasing evidence suggests that PrP C plays essential roles in the maintenance of metal homeostasis in the synapse. Trace elements have a crucial influence on the conformational change of PrP C . Given that other disease-related proteins such as β-amyloid protein and its precursor protein (APP) in Alzheimer's disease also exist in the synapse and possess a metal-binding ability, an interaction between PrP and metals and between PrP and APP, may occur in the synapse; the resulting metal homeostasis may lead to the pathogenesis of prion diseases. Here, we review our studies and other new findings that inform the current understanding of the link between trace elements and physiological functions of PrP C and the neurotoxicity of PrP Sc .

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“…Moreover, a binding of MPA to α-synuclein has been reported and causes missfolding of α-synuclein, a key protein in Parkinson's disease (Tavassoly and Lee 2012). It is possible that missfolded α-synuclein could alter gluramatergic NMDA-dependent signaling pathway like it has been shown for missfolded amyloid (Proft and Weiss 2012;Stys et al 2012;You et al 2012). …”

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confidence: 99%