Decrease in Peptide Methionine Sulfoxide Reductase in Alzheimer's Disease Brain

Gabbita, S. Prasad; Aksenov, Michael Y.; Lovell, Mark A.; Markesbery, William R.

doi:10.1046/j.1471-4159.1999.0731660.x

Cited by 243 publications

(165 citation statements)

References 41 publications

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“…3). Evidence supporting the possibility that MsrA may play an important role as an antioxidant in mammals comes from reports showing that reduction in MsrA activity occurs in very old rats (17) and in the brains of patients with Alzheimer's disease, which consequently leads to accumulation of carbonyl adducts in proteins (18). This phenomenon suggests that disruption of both MsrA and MsrB genes in mice should increase their vulnerability to oxidative stress even more.…”

Section: Discussionmentioning

confidence: 98%

Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals

Moskovitz

Barnoy²,

Williams³

et al. 2001

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

622

504

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Oxidation of proteins by reactive oxygen species is associated with aging, oxidative stress, and many diseases. Although free and protein-bound methionine residues are particularly sensitive to oxidation to methionine sulfoxide derivatives, these oxidations are readily repaired by the action of methionine sulfoxide reductase (MsrA). To gain a better understanding of the biological roles of MsrA in metabolism, we have created a strain of mouse that lacks the MsrA gene. Compared with the wild type, this mutant: (i) exhibits enhanced sensitivity to oxidative stress (exposure to 100% oxygen); (ii) has a shorter lifespan under both normal and hyperoxic conditions; (iii) develops an atypical (tip-toe) walking pattern after 6 months of age; (iv) accumulates higher tissue levels of oxidized protein (carbonyl derivatives) under oxidative stress; and (v) is less able to up-regulate expression of thioredoxin reductase under oxidative stress. It thus seems that MsrA may play an important role in aging and neurological disorders. P rotein-bound methionine residues are among the most susceptible to oxidation by reactive oxygen species (ROS), resulting in formation of methionine sulfoxide [Met(O)] residues. However, this modification can be repaired by methionine sulfoxide reductase (MsrA), which catalyzes the thioredoxindependent reduction of free and protein-bound Met(O) to methionine, both in vitro (1) and in vivo (2). Bacteria and yeast cells lacking the msrA gene show increased sensitivity to oxidative stress and lower survival rates (3, 4), with yeast showing accumulation of high levels of both free and protein-bound Met(O) (2, 4). In addition, overexpression of the MsrA enzyme in human T cells prolongs their life under conditions of oxidative stress (4). Because methionine residues are particularly susceptible to oxidation by ROS, MsrA could have at least three important functions in cellular metabolism: (i) as an antioxidant enzyme that scavenges ROS by facilitating the cyclic interconversion of methionine͞protein-methionine residues between oxidized and reduced forms (2); (ii) as a repair enzyme by keeping critical methionine residues in their reduced form; and (iii) as a regulator of critical enzyme activity through cyclic interconversion of specific methionine residues between oxidized and reduced forms (5, 6). Escherichia coli and Saccharomyces cerevisiae both contain at least two Msrs. One (MsrA) is able to reduce both free and protein-bound Met(O), and the other can reduce only free Met(O). The MsrA protein is highly expressed in liver, kidney, pigment epithelial cells of the retina, macrophages, cerebellum, and brain neurons (7). These tissues͞ cells are sensitive to oxidative stress damages. Therefore, abolishing the MsrA enzyme could lead to loss of antioxidant defense, resulting in enhanced oxidative damage and a decreased lifespan. To investigate the possible role of MsrA as an antioxidant in mammals and its possible influence on lifespan, we created a strain of mouse lacking the MsrA protein. Materials and ...

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Section: Discussionmentioning

confidence: 98%

Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals

Moskovitz

Barnoy²,

Williams³

et al. 2001

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

622

504

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“…Consistent with this hypothesis, we found that wildtype MsrA (but not two catalytically inactive mutants, C72S and C218S) protected dopaminergic neurons from two PD-related stresses: complex I inhibition and α-synuclein over-expression. Other groups have reported that MsrA is neuroprotective in vitro [21,50] and in vivo [25], and data from one study indicate that MsrA levels are decreased in the brains of Alzheimer's disease patients compared to age-matched controls [51]. A very recent study revealed that MsrA alleviates motor dysfunction and neurodegeneration in transgenic flies over-expressing α-synuclein [28].…”

Section: Discussionmentioning

confidence: 99%

Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

Liu

Hindupur

Nguyen

et al. 2008

Free Radical Biology and Medicine

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Parkinson's disease (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and α-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant α-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetyl-cysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant α-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD. Keywords aggresome; dopamine; glutathione; heat shock protein; methionine sulfoxide reductase; neurodegeneration; oxidative stress; Parkinson's disease; proteasome; protofibril; rotenone; synuclein Parkinson's disease (PD) is a neurologic disorder that involves a selective loss of dopaminergic neurons from the substantia nigra [1,2]. The postmortem brains of PD patients are characterized by reduced activity of mitochondrial complex I, an enzyme of the mitochondrial electron transport chain [3,4]. In turn, this defect may cause a 'leakage' of electrons from mitochondria, leading to the accumulation of reactive oxygen species (ROS) that damage *Corresponding author. Address: Jean-Christophe Rochet, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Drive, RHPH 410A, West Lafayette, Indiana, 47907-209147907- . Fax: 765-494-1414. E-mail: rochet@pharmacy.purdue.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2009 August 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript proteins, lipids, and nucleic acids [3,5]. The brains of PD patients also show evidence of impaired proteasomal function [6], a defect that results in increased oxidative stress and decreased elimination...

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“…In other reactions involving oxidation of the Met 35 formation of methionine sulfoxide (MetO) occurs, which can be reduced back to methionine by MetO reductase. The activity of MetO reductase is reduced in AD brain (161). AD brain, CSF, and plasma demonstrate increased levels of OS in AD (27,69,75,278).…”

Section: Application Of Redox Proteomics To Selected Neurodegenermentioning

confidence: 92%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

157

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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Decrease in Peptide Methionine Sulfoxide Reductase in Alzheimer's Disease Brain

Cited by 243 publications

References 41 publications

Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals

Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals

Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

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