Mechanisms by which metals promote events connected to neurodegenerative diseases

Campbell, Arezoo; Smith, Mark A.; Sayre, Lawrence M.; Bondy, Stephen C.; Perry, George

doi:10.1016/s0361-9230(01)00455-5

Cited by 94 publications

(45 citation statements)

References 112 publications

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“…A feature common to these diseases is the presence of redox active metals and concomitant increases in oxidative damage (52). Hemin-facilitated nitration of BSA occurred across a broad range of NO͞O 2 Ϫ fluxes (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\setlength{\oddsidemargin}{-69pt}\begin{document}\begin{equation}{\mathrm{_{2}^{-}}}\end{equation}\end{document} reaction

Thomas

Espey

Vitek

et al. 2002

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

176

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The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO ؊ ) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. nitrotyrosine ͉ nitric oxide ͉ peroxynitrite ͉ oxidation ͉ hemin N itrated tyrosine residues (NT) have been used as a marker of the involvement of nitric oxide (NO) and its related chemistry in a number of pathophysiological disorders including cardiovascular (1, 2) neurodegenerative and malignant conditions (1-5), such as septic shock (6), multiple sclerosis (7), Alzheimer's disease (8), and amyotrophic lateral sclerosis (9). In cancer the presence of NT often correlates with a poor prognosis (10), suggesting diagnostic implications.Several mechanisms for NT formation have been proposed, and its origin remains controversial (11-16). Detection of NT in vitro following exposure to synthetic peroxynitrite (ONOO Ϫ ) initially suggested that the reaction of NO with superoxide (O 2 Ϫ ) may be the primary source of NT (17,18). Further studies demonstrated that cogeneration of NO and O 2 Ϫ gave dissimilar results than bolus synthetic ONOO Ϫ (12,19,20). These disparities in nitration yields arose from further reactions of ONOO Ϫ with excess NO or O 2 Ϫ (21). Given the complexity of this seemingly simple reaction, much debate has ensued over the likelihood of NT formation under biologically relevant conditions (12,14).In addition to a ONOO Ϫ -mediated pathway, NT formation has been shown to result from the catalysis of nitrite oxidation by peroxidases, thus providing an alternate mechanism for its formation in vivo (22-24). Although leukocyte peroxidases likely account for a substantial amount of NT production in vivo, this mechanism fails to explain NT formation in the absence of inflammatory cells or peroxidases [i.e., a MPO Ϫ/Ϫ mouse model (25)].NT has been shown to occur on distinct proteins rather than in an indiscriminate manner (26). This may result from variations in protein susceptibility to nitration due to conformational differences or to association with redox active metals (27,28). We evaluated the relative efficacy of the synthetic ONOO Ϫ , NO͞O 2 Ϫ cogeneration, peroxidase, and redox active metal pathways to promote NT formation. Materials and MethodsBSA (essentially globulin-free), ribonuclease A, ferriprotoporphyrin IX (hemin), superoxide dismutase (SOD; bovine erythrocytes), cytochrome c, horseradish peroxidase (HRP), catalase (Cat), hypoxanthine (HX), myoglobin (horse heart), 2,2Ј-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), FeSO 4 , diethylenetriaminepentaacetic acid (DTPA), dimethylformamide (DMF), ␤-amyloid (1-42) protein (A␤), MnO 2 , and CuCl 2 were purchased from Sigma-Aldrich. H 2 O 2 , NaHCO 3 , NaNO 2 , and FeCl 3 were from Fisher Scientific....

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Section: Discussionmentioning

confidence: 99%

“…This process may have potential importance in the pathogenesis of several neurodegenerative disorders, especially in Alzheimer's disease, where metals are a prominent etiologic feature (52). Iron and copper levels have been measured as high as 0.4 and 1.0 mM, respectively, in the brains of Alzheimer's patients (56).…”

Section: Discussionmentioning

confidence: 99%

Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\setlength{\oddsidemargin}{-69pt}\begin{document}\begin{equation}{\mathrm{_{2}^{-}}}\end{equation}\end{document} reaction

Thomas

Espey

Vitek

et al. 2002

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

176

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“…Additionally, oxidative stress is likely to be an important factor during neurodegeneration (reviewed in ref. 35), yet the causes of any of these are still not clear.…”

Section: Discussionmentioning

confidence: 99%

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

Atamna¹,

Killilea²,

Killilea³

et al. 2002

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

199

150

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Heme, a major functional form of iron in the cell, is synthesized in the mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX. Heme deficiency was induced with N-methylprotoporphyrin IX, a selective inhibitor of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373 (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in brain cells decreases mitochondrial complex IV, activates nitric oxide synthase, alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The metabolic consequences resulting from heme deficiency seem similar to dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of heme in these observations could result from its interaction with heme regulatory motifs in specific proteins or secondary to the compromised mitochondria. Common causes of heme deficiency include aging, deficiency of iron and vitamin B6, and exposure to toxic metals such as aluminum. Iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus, heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.iron ͉ complex IV ͉ amyloid precursor protein (APP) ͉ nitric oxide synthase ͉ oxidative stress

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“…Although the mechanisms of epileptic convulsions have been a subject of intensive investigations for many years in most cases the etiology of the disease is not known [1].Metallic elements participating in the processes like: oxidative stress, excitotoxicity, mitochondrial dysfunction or protein aggregation may lead to the atrophy and death of neurons in case of some neurodegenerative disorders [2][3][4]. Because epileptic seizures induce neurodegeneration in selected areas of brain it is suspected that metals may be involved in the pathogenesis and progress of epilepsy as well [5].…”

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confidence: 99%

The role of trace elements in the pathogenesis and progress of pilocarpine-induced epileptic seizures

et al. 2008

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Epilepsy, the third most common neurological disorder, is characterized by recurrent unprovoked seizures. Although the mechanisms of epileptic convulsions have been a subject of intensive investigations for many years in most cases the etiology of the disease is not known [1].Metallic elements participating in the processes like: oxidative stress, excitotoxicity, mitochondrial dysfunction or protein aggregation may lead to the atrophy and death of neurons in case of some neurodegenerative disorders [2][3][4]. Because epileptic seizures induce neurodegeneration in selected areas of brain it is suspected that metals may be involved in the pathogenesis and progress of epilepsy as well [5].Existing evidence suggests that epileptic seizures significantly change metabolism and distribution of trace elements in the nervous tissue [6][7][8]. From the other hand, content of metals determinates susceptibility to convulsions [9].In our experiment we used pilocarpine in order to induce epilepsy in rats. In order to find what elements are involved in the pathogenesis and progress of epileptic convulsions the comparison between pilocarpine treated and control rats was done. The samples of rat brain were cut using a cryomicrotome into 15 µm thick slices. Thin tissue sections were mounted on Ultralene foil and freeze-dried.X-ray fluorescence microscopy was employed for topographic and quantitative analysis of selected metals in the areas of brain tissue involved in epilepsy. The measurements were done on the bending magnet beamline L at HASYLAB. The multilayer monochromator was applied and the primary photon energy was set to 17 keV. The beam was focused with polycapillary optics for a final beam spot dimension of 15 µm x 15 µm. The characteristic X-ray lines were measured using the Vortex SDD detector from SII Nano Technology USA inc. and the time of spectra acquisition was equal to 6 s per pixel. Measurements of NIST standard reference materials (SRM 1833 and SRM 1832) were performed for spectrometer calibration.The elements such us P, S, Cl, K, Ca, Fe, Cu, Zn, Br, Rb and Sr were detected in rat brain sections. For each sample two-dimensional analysis of elemental distribution was performed for the area of hippocampus and brain cortex. The results of such analysis for selected control and epileptic sample were shown in Figures 1 and 2 respectively.For four regions of hippacampus formation (CA1 -Cornu Ammonis, CA3, DG -Dentate Gyrus and H -Hilus) and motor cortex the mean masses per unit area were evaluated. The areas taken into account in calculations were equal to 300 µm per 300 µm. The preliminary results showed that the level of Ca tends to be higher for CA1 region of hippocampus and cortex in case of animals with pilocarpine induced epilepsy. The opposite relation was observed for Zn level in the area of DG.1551

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Mechanisms by which metals promote events connected to neurodegenerative diseases

Cited by 94 publications

References 112 publications

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

The role of trace elements in the pathogenesis and progress of pilocarpine-induced epileptic seizures

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