The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy

Gaeta, Alessandra; Hider, Robert C.

doi:10.1038/sj.bjp.0706416

Cited by 370 publications

(265 citation statements)

References 169 publications

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“…The exact physiological roles of PrP C are still under investigation, but many studies have suggested its participation in the metabolism of metals and its role as antioxidant (superoxide dismutase (SOD)-like activity). [6][7][8][9][10] Although the potential redox activity of PrP C has been previously demonstrated, this is controversial since other studies dispute the SOD function of PrP C . 11,12 The interaction of PrP C with metals such as iron (Fe), copper (Cu) and manganese (Mn) is important, since these metals serve as cofactors for enzymes, and play important roles in mammalian biochemical processes.…”

Section: Introductionmentioning

confidence: 93%

“…10,[17][18][19] Moreover, TSE neurotoxicity, associated with imbalance in brain homeostasis and deregulation of metals, has been previously observed for other neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). 9 PrP C -metal interactions differ with each metal and may play a physiological or pathological role. For example, binding of PrP C to Cu is linked to PrP C stability and antioxidant activity at brain synapses, protecting the cells from oxidative damage and neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

“…19,22 Moreover, the loss of PrP C functions may increase intracellular free radicals and oxidative damage. 9,18 TSEs like Scrapie and Sporadic CreutzfeldtJacob disease have been linked to changes in Fe metabolism that contribute to accumulation of PrP Sc , sequestration of Fe in PrP Sc -ferritin complexes, and neurotoxicity associated to upregulation of Fe intake into the brain. 10,17 Furthermore, Fe binding to PrP C contributes to conformational changes that provide PrP Sc stability and resistance to proteinase K (PK) digestion.…”

Section: Introductionmentioning

confidence: 99%

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Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Rivera

Novakofski

Weng

et al. 2015

Prion

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ABSTRACT. Prion proteins (PrP C ) are cell membrane glycoproteins that can be found in many cell types, but specially in neurons. Many studies have suggested PrP C 's participation in metal transport and cellular protection against stress in the central nervous system (CNS). On the other hand PrP Sc , the misfolded isoform of PrP C and the pathogenic agent in transmissible spongiform encephalopathies (TSE), has been associated with brain metal dyshomeostasis in prion diseases. Thus, changes in metal concentration associated with protein misfolding and aggregation have been reported for human and animal prion diseases, as well as for other neurodegenerative disorders, such as Parkinson's and Alzheimer's disease. The use of metal concentrations in tissues as surrogate markers for early detection of TSEs has been suggested. Studies on the accumulation of metals in free-ranging white-tailed deer have not been conducted. This study established concentrations of copper, iron, manganese, and magnesium in 2 diagnostic tissues used for CWD testing (obex and retropharyngeal lymph nodes (RLN)). We compared these concentrations between tissues and in relation to CWD status. We established reference intervals (RIs) for these metals and explored their ability to discriminate between CWD-positive and CWD-negative animals. Our results indicate that independent of CWD status, white-tailed deer accumulate higher concentrations of Fe, Mn and Mg in Ó Nelda A Rivera, Jan Novakofski, Hsin-Yi Weng, Amy Kelly, Damian Satterthwaite-Phillips, Marilyn O Ruiz, and Nohra Mateus-Pinilla *Correspondence to: Nohra Mateus-Pinilla; Email:nohram@illinois.edu Received November 21, 2014; Revised January 25, 2015; Accepted February 9, 2015. Color versions of one or more figures in this article can be found online at www.tandfonline.com/kprn. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. ISSN: 1933-6896 print / 1933-690X online DOI: 10.1080/19336896.2015 RLN than in obex. White-tailed deer infected with CWD accumulated significantly lower concentrations of Mn and Fe than CWD-negative deer. These patterns differed from other species infected with prion diseases. Overlapping values between CWD positive and negative groups indicate that evaluation of these metals in obex and RLN may not be appropriate as a diagnostic tool for CWD infection in white-tailed deer. Because the CWD-negative deer were included in constructing the RIs, high specificities were expected and should be interpreted with caution. Due to the low sensitivity derived from the RIs, we do not recommend using metal concentrations for disease discrimination.Prion, 9:48-58, 2015 Published with license by Taylor & Francis Group, LLC

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Rivera

Novakofski

Weng

et al. 2015

Prion

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“…and nitric oxide (NO . ) in addition to hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO -) [7]. These are highly unstable species that react with lipids, proteins, RNA and DNA.…”

Section: Introductionmentioning

confidence: 99%

Oncoprotective Role of Chelation Therapy in Hypoxic Solid Tumors: A Theoretical Model

Gupta¹,

Kapoor²,

Chaudhary³

et al. 2012

IJBBB

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Abstract-Solid tumors show areas of differential blood supply due to decreasing vascularisation from periphery towards the core. As a result, a gradient of oxygen is formed such that internal areas with low oxygen tension lead to altered physiochemical conditions. This state of low oxygen-called hypoxia-is gaining interest due to a large scale shift in metabolism of the tumor cells. Reactive Oxygen Species (ROS) thus produced cause extensive DNA damage in hypoxic core regions, exacerbating the aggressiveness of cancer by accumulation of mutations. We show how the ubiquitous cellular enzyme Catalase may prevent ROS mediated damage through chelation of metal ions. Metal ions are known to increase oxidative stress in a cell and recent reports implicated involvement of metal ions in controlling p53 function. We propose that chelation therapy in solid tumors can delay the accumulation of mutations by catalase mediated decrease in ROS levels and by rescuing the p53 activity in a cell.Index Terms-Catalase, chelation, hypoxia, oxidative stress. I. INTRODUCTIONCancer is a multigenic process which involves the accumulation of several mutations which offer a competitive advantage to the cancerous cell over normal cells. The accumulation of mutations in the DNA relate to the pathogenesis of the disease. However, a number of cellular mechanisms-called cell cycle checkpoints-ensure that an abnormal cell does not proceed towards cell division either by forcing these cells into cell-cycle arrest or apoptosis [1]. Multiple mutations are thus required to transform a normal cell into a cancer cell that increase the cancer's clinical aggressiveness-that is conversion from the relatively innocuous benign tumors to debilitating metastatic cancers. Also, a loss of heterozygocity (LOH) [2] is seen in cancers which impair both alleles of genes which otherwise show normal phenotype in heterozygous state.Solid tumors are cancerous growths in the form of sarcomas, carcinomas and lymphomas that contain an abnormal mass of tissue devoid of liquid area [3]. Rapid proliferation of cells that form the tumor cause internal areas to be poorly vascularized [4]. The low blood supply established to internal areas of the tumor causes a shortage of various nutrients including oxygen. The decrease in oxygen supply from about 2.5-9 percent oxygen tension to less than 1 percent is called hypoxia [5]. As oxygen is critical for cellular energetics, hypoxia is reported to alter metabolic state of a cell and hence a marked level of oxidative stress is seen due Cells possess several enzymes that utilize the ROS species as substrates and form products that are harmless to the cell. The various enzymes include catalase, superoxide dismutase and glutathione. Our study involves the use of the enzyme catalase. Catalase catalyses the breakdown of hydrogen peroxide to water and molecular oxygen. This enzyme has one of the highest turnover number in that it catalyses the breakdown of millions of substrate molecules to products per second [8]. This activity is critica...

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“…Because all prion disorders except vCJD have a relatively long incubation period, effective treatment can be initiated much before clinical symptoms appear. Given the focus of this review, two possible avenues hold promise: (a) antioxidants and free radical scavengers (63,139,214), and (b) metal chelators (38,65,248). Limited studies conducted in this direction have been quite promising and are reviewed here.…”

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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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The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy

Cited by 370 publications

References 169 publications

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Oncoprotective Role of Chelation Therapy in Hypoxic Solid Tumors: A Theoretical Model

Redox Control of Prion and Disease Pathogenesis

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