Redox Control of Prion and Disease Pathogenesis

Singh, Neena; Singh, Ajay Vikram; Das, Debarshi; Mohan, Maradumane L

doi:10.1089/ars.2009.2628

Cited by 59 publications

(38 citation statements)

References 257 publications

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“…Although PrP C does not appear to bind iron under in vivo conditions (412), recent studies on cell and mouse models indicate that PrP C promotes iron uptake and transport in neuroblastoma cells in culture, and uptake by hematopoietic precursors and parenchymal cells of major organs in mouse models (408,409). When over-expressed in neuroblastoma cells, PrP C increases the labile iron pool and iron saturation of ferritin.…”

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

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176

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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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

Self Cite

176

165

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“…Despite not being fully elucidated, the mechanism underlying PrDs pathogenesis has been associated with a complex array of processes operating simultaneously and synergistically [31]. These include: PrP C →PrP Sc conversion [5,66]; PrP Sc aggregation [8,67]; OS, accompanied by lipid and protein oxidation [68][69][70][71][72] and reduced levels of potent free-radical scavenger, such as polyunsaturated fatty acids, α-tocopherol, and glutathione [73]; unbalance of metal ions [74]; and brain inflammation with activation of astrocytes and microglia [75].…”

Section: From Bivalent To Mtlsmentioning

confidence: 99%

Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

2014

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Prion diseases (PrDs) are fatal neurodegenerative disorders, for which no effective therapeutic and diagnostic tools exist. The main pathogenic event has been identified as the misfolding of a disease-associated prion protein. Nevertheless, pathogenesis seems to involve an intricate array of concomitant processes. Thus, it may be unlikely that drugs acting on single targets can effectively control PrDs. In addition, diagnosis occurs late in the disease process, by which point it is difficult to determine a successful therapeutic intervention. In this context, multitarget ligands (MTLs) and theranostic ligands (TLs) emerge for their potential to effectively cure and diagnose PrDs. In this review, we discuss the medicinal chemistry challenges of identifying novel MTLs and TLs against PrDs, and envision their impact on prion drug discovery.

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“…Moreover, this species is known to be susceptible to severe neurodegenerative diseases such as scrapie and MaediVisna in which oxidative stress plays a pivotal role. In particular, an imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals such as iron and copper have been shown to be involved in several neurodegenerative conditions, including prion disorders (Singh et al 2010). Additionally, in vitro cultures of neural cells from sheep have been previously performed in order to clarify the mechanisms underlying neuronal ceroid lipofuscinosis (Batten disease), widely known as a neurodegenerative disorder occurring both in sheep and in humans and characterized by abnormal fluorescence storage bodies in many types of cells, including neurons Hughes et al 1999).…”

Section: Resultsmentioning

confidence: 99%

Aromatase expression in cultured fetal sheep astrocytes after nitrosative/oxidative damage

et al. 2011

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Aromatase, the enzyme converting androgens into estrogens, is involved in many brain processes such as neural differentiation and plasticity or the prevention of cell death. We have previously observed an increase in aromatase immunoreactivity in sheep neurons exposed in vitro to the oxidant 3-nitro-L: -tyrosine. However, little is known regarding the way that sheep astrocytes cope with nitrosative stress, a condition occurring in sheep in the pathogenesis of neurodegenerative disorders such as scrapie and Maedi-Visna. Our aim has been to evaluate the effects of 3-nitro-L-tyrosine on astrocyte primary cultures from 90-day-old fetal sheep brain. Living cells were observed and characterized by immunofluorescence with a GFAP antibody, which indicated that the majority of the cells were astrocytes. A viability assay was performed on both untreated and treated cells. Reverse transcription with the polymerase chain reaction was undertaken to monitor time- and dose-dependent variations in aromatase gene expression. Stressed astrocytes showed signs of deterioration, were reduced in number, and appeared round with few short processes; the cell death rate was ∼30%. Aromatase expression was detected starting from a 24-h exposure to 1 mM 3-nitro-L-tyrosine and reached the highest levels at 72 h. Thus, oxidative damage probably results in the local production of neuroprotective estradiol by reactive astrocytes via the aromatization of testosterone.

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Redox Control of Prion and Disease Pathogenesis

Cited by 59 publications

References 257 publications

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

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

Multitarget Ligands and Theranostics: Sharpening the Medicinal Chemistry Sword Against Prion Diseases

Aromatase expression in cultured fetal sheep astrocytes after nitrosative/oxidative damage

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