Elevated manganese levels in blood and CNS in human prion disease

Hesketh, Shirley; Sassoon, Judyth; Knight, Rob; Brown, David R.

doi:10.1016/j.mcn.2007.12.008

Cited by 62 publications

(57 citation statements)

References 53 publications

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“…This is the first study to identify a bacterial manganese binding MSCRAMM. Because a higher concentration of free manganese would be an oxidative stress in the cells (52), the concentration of free manganese in vivo is extremely low (10 Ϫ7 M) (53). In addition, manganese is a trace element and is present at very low levels in the environment (10 Ϫ7 M) (52).…”

Section: Discussionmentioning

confidence: 99%

Manganese Binds to Clostridium difficile Fbp68 and Is Essential for Fibronectin Binding

Lin¹,

Kuo²,

Koleci³

et al. 2011

Journal of Biological Chemistry

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Clostridium difficile is an etiological agent of pseudomembranous colitis and antibiotic-associated diarrhea. Adhesion is the crucial first step in bacterial infection. Thus, in addition to toxins, the importance of colonization factors in C. difficileassociated disease is recognized. In this study, we identified Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects people and multiple animal species. Colonization of the gastrointestinal tract may be asymptomatic or cause a variety of disorders, including mild diarrhea, pseudomembranous colitis, and antibiotic-associated diarrhea (1). Recent outbreaks in North America and Europe document the seriousness of C. difficile infection (2). C. difficile toxins, including toxin A, toxin B, and a recently identified toxin, binary ADP-ribosyltransferase toxin C. difficile transferase, are thought to be the primary virulence factors that mediate C. difficile-associated disease (3). Because C. difficile colonizes gastrointestinal tissues and enterocyte-like Caco-2 cells (4, 5), colonization factors are also recognized as important virulence factors of C. difficile. A variety of colonization factors has been identified, including the following: capsule (6); proteolytic enzymes (7, 8); S-layer proteins P36 and P47 (9); adhesins such as SLPA, CCAP6, Fbp68, and 12-kDa protein (4, 9 -14); flagellins such as FliC and FliD (15, 16); and GroEL chaperones (17,18).Adhesion is the first step in bacterial infection, and several adhesins known as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) 2 contribute to this step (19). MSCRAMMs located on bacterial surfaces mediate adhesion by binding to various extracellular matrices including fibronectin (Fn), laminin, collagen, elastin, and proteoglycan on host surfaces (19). Loss of some of these genes may attenuate virulence, indicating that MSCRAMMs are pivotal mediators of bacterial disease (20). Although a number of MSCRAMMs have been investigated in other bacterial pathogens, only a few clostridial adhesins, such as Fbp68, have been characterized, and the colonization mechanisms of C. difficile are still poorly understood (11).Manganese-binding proteins are important players in bacterial physiology by participating in cation homeostasis (21), carbon metabolism to promote nutrient acquisition (22), signal transduction (23), resistance to oxidative stress (24), and nutrient-deprived stress (25). In addition, the interaction of some bacterial adhesins and ECM components can be modulated by metal ions such as calcium (26,27). To date, the ability of manganese to mediate bacterial adhesion has not been reported.Previously, Fbp68 on the surface of C. difficile was shown to serve as an adhesin by binding to Fn, fibrinogen, and vitronectin (11). Interestingly, antibody to Fbp68 can be detected in sera from patients with C. difficile-associated disease, indicating that Fbp68 can induce a host immune response during C. difficile infection (28). Structural analysis of Fbp68 indicates t...

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Section: Discussionmentioning

confidence: 99%

Manganese Binds to Clostridium difficile Fbp68 and Is Essential for Fibronectin Binding

Lin¹,

Kuo²,

Koleci³

et al. 2011

Journal of Biological Chemistry

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“…Manganese binding to PrP also increases its survival in the environment and increases its ability to cause prion infection in cells [129]. Studies looking at the levels of trace elements in the brains of animals with BSE, sheep scrapie, patients with CJD or vCJD, and rodents experimentally infected with scrapie all show a similar trend [130][131][132]. They indicate reduced levels of copper and increased levels of manganese.…”

Section: Prion Diseasesmentioning

confidence: 93%

Iron, Aging, and Neurodegeneration

Angelova

Brown

2015

Metals

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Abstract:Iron is a trace element of considerable interest to both chemistry and biology. In a biological context its chemistry is vital to the roles it performs. However, that same chemistry can contribute to a more deleterious role in a variety of diseases. The brain is a very sensitive organ due to the irreplaceable nature of neurons. In this regard regulation of brain iron chemistry is essential to maintaining neuronal viability. During the course of normal aging, the brain changes the way it deals with iron and this can contribute to its susceptibility to disease. Additionally, many of the known neurodegenerative diseases have been shown to be influenced by changes in brain iron. This review examines the role of iron in the brain and neurodegenerative diseases and the potential role of changes in brain iron caused by aging.

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“…In addition, PrP C reduces Cu 2 + to Cu 1 + prior to transport via copper-specific intracellular trafficking proteins, suggesting a dual function in copper uptake and reduction to facilitate transport across the endosomal membrane (307). The interaction of PrP C with other metals such as manganese, iron, zinc, and nickel, and the physiological implications of this interaction are poorly understood (85,198). The majority of these metals induce aggregation of purified or recombinant PrP C to a form resembling PrP Sc under certain conditions, but the contribution of these metals to prion disease pathogenesis in vivo is unclear.…”

Section: E Sporadic Creutzfeldt-jakob Diseasementioning

confidence: 99%

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

Singh

Haldar

Tripathi

et al. 2014

Antioxidants & Redox Signaling

184

165

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Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mismetabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324Signal. 20, -1363

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Elevated manganese levels in blood and CNS in human prion disease

Cited by 62 publications

References 53 publications

Manganese Binds to Clostridium difficile Fbp68 and Is Essential for Fibronectin Binding

Manganese Binds to Clostridium difficile Fbp68 and Is Essential for Fibronectin Binding

Iron, Aging, and Neurodegeneration

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

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