Copper binding to PrPC may inhibit prion disease propagation

Hijazi, Nuha; Shaked, Yuval; Rosenmann, Hana; Ben‐Hur, Tamir; Gabizon, Ruth

doi:10.1016/j.brainres.2003.09.014

Cited by 93 publications

(96 citation statements)

References 48 publications

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“…It was observed that neuroblastoma cells cultured in the presence of copper ions lost the ability to bind and internalize PrP Sc , thereby evading infection and toxicity. A significant delay in the onset of clinical disease also was observed in scrapie-infected hamsters given a dietary supplement of copper (91), supporting these observations. It is likely that the protective effect of copper reflects internalization and degradation of PrP C on exposure to copper, the substrate for PrP Sc generation, although a direct effect on the generation of PrP…”

Section: B Metal Chelatorssupporting

confidence: 70%

“…For example, exposure of purified PrP C to copper induces its conversion to a form similar to PrP Sc (177), whereas addition of copper to synthetic prions slows the formation of amyloid, indicating an inhibitory role (21,159). When added to scrapie-infected cells, copper reduces the accumulation of PrP Sc (91), whereas in scrapie-infected mouse brains, copper is associated with PrP Sc deposits, and chelation of copper delays the onset of prion disease (201). In addition, copper induces the interconversion of PrP Sc strains in vitro from clinically distinct subtypes of CJD, most likely by altering their metalion occupancy and secondary structure (230).…”

Section: A Prp and Metal Interaction: The Ironic Connectionmentioning

confidence: 99%

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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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Section: B Metal Chelatorssupporting

confidence: 70%

Section: A Prp and Metal Interaction: The Ironic Connectionmentioning

confidence: 99%

Redox Control of Prion and Disease Pathogenesis

Singh

Das

et al. 2010

Antioxidants & Redox Signaling

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“…Copper is known to promote prion infectivity (15), yet it is also important in limiting neuropathology caused by reactive oxygen species (16). Although copper chelation delays disease onset in mice (17), similar delays are observed in mice and hamsters maintained on a high-copper diet (18,19). Mice fed a copper-depleted diet are also reported to be more sensitive to prion pathogenesis following i.p.…”

mentioning

confidence: 99%

Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease

Siggs

Cruite

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Copper influences the pathogenesis of prion disease, but whether it is beneficial or detrimental remains controversial. Copper homeostasis is also essential for normal physiology, as highlighted by the spectrum of diseases caused by disruption of the copper transporting enzymes ATP7A and ATP7B. Here, by using a forward genetics approach in mice, we describe the isolation of three alleles of Atp7a , each with different phenotypic consequences. The mildest of the three, Atp7a brown , was insufficient to cause lethality in hemizygotes or mottling of the coat in heterozygotes, but did lead to coat hypopigmentation and reduced copper content in the brains of hemizygous males. When challenged with Rocky Mountain Laboratory scrapie, the onset of prion disease was delayed in Atp7a brown mice, and significantly less proteinase-resistant prion protein was found in the brains of moribund Atp7a brown mice compared with WT littermates. Our results establish that ATP7A-mediated copper homeostasis is important for the formation of pathogenic proteinase-resistant prion protein.

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“…Treatment of scrapie-infected mice with the copper chelator D-(-)-penicillamine delayed the onset of prion disease (36), supporting the notion that copper exerts a prion promoting effect. However, copper administration to scrapie-infected hamsters delays the onset of prion disease (41), suggesting a beneficial role of copper against prion disease progression.…”

Section: Copper and Prion Diseasesmentioning

confidence: 99%

Copper brain homeostasis: Role of amyloid precursor protein and prion protein

Inestrosa

Cerpa

Varela-Nallar

2005

IUBMB Life (International Union of Biochemistry and Molecular B

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The main proteins associated with Alzheimer's and prion diseases (amyloid precursor protein (APP) and prion protein (PrPC), respectively, have binding sites for copper and it has therefore been suggested that they play a role in copper metabolism. Here, we review evidence indicating that the copper binding domains (CuBD) of APP and PrPC are able to modulate the oxidation state of copper, and prevent neurotoxic effects and memory impairments induced by copper. Results with transgenic and other animal models have established the relation between these pathogenic proteins and copper. In particular, APP transgenic models, suggest a beneficial effect for copper in AD. IUBMB Life, 57: 645‐650, 2005

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Copper binding to PrPC may inhibit prion disease propagation

Cited by 93 publications

References 48 publications

Redox Control of Prion and Disease Pathogenesis

Redox Control of Prion and Disease Pathogenesis

Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease

Copper brain homeostasis: Role of amyloid precursor protein and prion protein

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