Cellular prion protein function in copper homeostasis and redox signalling at the synapse

Vassallo, Neville; Herms, Jochen

doi:10.1046/j.1471-4159.2003.01882.x

Cited by 186 publications

(184 citation statements)

References 60 publications

(114 reference statements)

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“…However, its presence and its putative role at the synapse are controversial (Fournier et al, 1995;Laine et al, 2001;Vassallo and Herms, 2003). For example, in CJD patients, an abnormal form of PrP c accumulates at synaptic terminals (Kitamoto et al, 1992), which suggest that loss of natural function of PrP c or PrP c -mediated processes at the synaptic terminals is responsible for neuronal dysfunction and degeneration in this disease (Kitamoto et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, PrP c , by Cu 2+ binding, may participate in the control of calcium flux and redox stage of the presynaptic terminal (Vassallo and Herms, 2003). Lastly, pioneering electrophysiological studies (using PrP c knockout slices) by Collinge established that PrP c participates in long-term potentiation (Collinge et al, 1994;Curtis et al, 2003;Maglio et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

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“…of PrP C is unknown, but recent investigations focus on the ability of the octarepeat domain to take up copper (5,(7)(8)(9)(10)(11). PrP C protects against apoptosis (12) and radical-mediated oxidative damage (13,14) and even stimulates nerve cell growth and development (15).…”

mentioning

confidence: 99%

The Affinity of Copper Binding to the Prion Protein Octarepeat Domain: Evidence for Negative Cooperativity

2006

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The prion protein (PrP) binds Cu 2+ in its N-terminal octarepeat domain, composed of four or more tandem PHGGGWGQ segments. Previous work from our laboratory demonstrates that copper interacts with the octarepeat domain through three distinct coordination modes at pH 7.4, depending upon the precise ratio of Cu 2+ to protein. Here, we apply both electron paramagnetic resonance (EPR) and fluorescence quenching to determine the copper affinity for each of these modes. At low copper occupancy, which favors multiple His coordination, the octarepeat domain binds Cu 2+ with a dissociation constant of 0.10 (±0.08) nM. In contrast, high copper occupancy, involving coordination through deprotonated amide nitrogens, exhibits a weaker affinity characterized by dissociation constants in the range of 7.0-12.0 μM. Decomposition of the EPR spectra reveals the proportions of all coordination species throughout the copper concentration range and identifies significant populations of intermediates, consistent with negative cooperativity. At most copper concentrations, the Hill coefficient is less than 1.0 and approximately 0.7 at half copper occupancy. These findings demonstrate that the octarepeat domain is responsive to a remarkably wide copper concentration range covering approximately 5 orders of magnitude. Consideration of these findings, along with the demonstrated ability of the protein to quench copper redox activity at high occupancy, suggests that PrP may function to protect cells by scavenging excess copper.The prion protein (PrP) 1 is responsible for a novel class of infectious, neurodegenerative diseases collectively known as the transmissible spongiform encephalopathies (TSEs) (1-3). The TSEs include scrapie in sheep, mad cow disease (bovine spongiform encephalopathy, BSE), chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans. The normal cellular form of the prion protein, referred to as PrP C , is found in a wide range of tissues of all mammalian and avian species. A misfolding event converts the protein to the infectious, β-sheet-rich scrapie form (PrP Sc ) responsible for the TSEs.PrP C is a GPI-anchored glycoprotein expressed in abundance on the surface of neurons, predominantly on presynaptic membranes (4,5). The mature form of PrP, consisting of residues 23-231 in hamster, has a globular C-terminal domain and a largely unstructured N-terminal domain (6) (Figure 1). The C-terminal domain (residues 125-231) contains three α helices, two of which are stabilized by a single interhelical disulfide bond, and a small antiparallel β sheet. The flexible N-terminal domain is glycine-rich and highly flexible. Within the flexible N-terminal region of PrP is the octarepeat domain, composed of four or five highly conserved, contiguous repeats of the eight-residue sequence PHGGGWGQ. The physiological function

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“…A plausible explanation for these disparate findings could be that PrP C alters the distribution of copper rather than its overall content in the brain, as observed for zinc (179). This assumption is supported by the fact that the copper content of synaptosomal membranes that express high levels of PrP C is twofold higher in wild-type mice compared with PrP À=À mice, an observation that has prompted the suggestion that PrP C regulates copper concentration at the synapse by serving as a sink for excess copper ions released during synaptic vesicle fusion (117,228). Such a function would maintain physiologically safe levels of copper in presynaptic cytosol, a site that is exposed to high concentrations of copper because of release of copper ions from nerve endings after depolarization.…”

Section: A Prp and Copper Interactionmentioning

confidence: 93%

“…However, enough evidence exists to implicate PrP C in redox reactions that serve the general purpose of intracellular signaling (174,193), protection against oxidative stress (120,219), and modulation of synaptic activity (85,117,228). The redox potential of PrP C is mainly because of its association with redox-active metals such as copper and iron, although PrP is known to interact with other metals, including zinc, manganese, and nickel (23,29,97,233).…”

Section: Redox Control Of Prion Protein: Physiological Implicationsmentioning

confidence: 99%

Redox Control of Prion and Disease Pathogenesis

Singh

Das

et al. 2010

Antioxidants & Redox Signaling

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Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several neurodegenerative conditions, including prion disorders. Whereas some reports attribute this to end-stage disease, others provide evidence for specific mechanisms leading to brain metal dyshomeostasis during disease progression. In prion disorders, imbalance of brain-iron homeostasis is observed before end-stage disease and worsens with disease progression, implicating ironinduced oxidative stress in disease pathogenesis. This is an unexpected observation, because the underlying cause of brain pathology in all prion disorders is PrP-scrapie (PrP Sc ), a b-sheet-rich conformation of a normal glycoprotein, the prion protein (PrP C ). Whether brain-iron dyshomeostasis occurs because of gain of toxic function by PrP Sc or loss of normal function of PrP C remains unclear. In this review, we summarize available evidence suggesting the involvement of oxidative stress in prion-disease pathogenesis. Subsequently, we review the biology of PrP C to highlight its possible role in maintaining brain metal homeostasis during health and the contribution of PrP Sc in inducing brain metal imbalance with disease progression. Finally, we discuss possible therapeutic avenues directed at restoring brain metal homeostasis and alleviating metal-induced oxidative stress in prion disorders. Antioxid. Redox Signal. 12, 1271-1294.

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Cellular prion protein function in copper homeostasis and redox signalling at the synapse

Cited by 186 publications

References 60 publications

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

The Affinity of Copper Binding to the Prion Protein Octarepeat Domain: Evidence for Negative Cooperativity

Redox Control of Prion and Disease Pathogenesis

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