Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation

Yermolaieva, Olena; Xu, Rong; Schinstock, Carrie A.; Brot, Nathan; Weissbach, Herbert; Heinemann, Stefan H.; Hoshi, Toshinori

doi:10.1073/pnas.0308215100

Cited by 152 publications

(132 citation statements)

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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%

“…MsrA is present throughout the brain, including the substantia nigra [19]. Cells with increased or decreased levels of MsrA are relatively resistant or vulnerable to oxidative insults, respectively [18,[20][21][22][23]. MsrA protects cells from oxidative stress not only by repairing proteins damaged by methionine oxidation, but also by engaging in a cycle of methionine oxidation and reduction that ultimately results in ROS scavenging [18,22].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Nih-pa Author Manuscriptmentioning

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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“…Reactive oxygen species (ROS) promote oxidative damage and contribute to tissue destruction in a wide variety of diseases [10], including steatohepatitis [16]. GSH, a potent endogenous antioxidant which neutralizes free radicals, is severely depleted in a variety of forms of liver injury, acetaminophen hepatotoxicity serving as the prototype [12].…”

Section: Discussionmentioning

confidence: 99%

“…Methionine, a sulfur amino acid which is converted to cysteine, serves as a precursor for the biosynthesis of GSH. Reactive oxygen species (ROS) promote oxidative damage in varying cellular constituents, including amino acids, lipids, and nucleic acids, and play a critical role in the development of liver injury [9,10]. S-adenosylmethionine (also termed AdoMet, SAMe, and SAM); SAMe will be used to denote both the natural metabolite and therapeutic agent in this article is an over-the-counter complementary and alternative medicine (CAM) agent.…”

Section: Introductionmentioning

confidence: 99%

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups ( p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-␣1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and TGF-␤) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. C

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“…Over-expression of MsrA has also been shown to increase resistance to oxidative stress in WI-38 SV40 fibroblasts (Picot et al, 2005) and yeast and human T cells (Moskovitz et al, 1998). MsrA repair has been shown to protect against hypoxia/reoxygenation in neuronal cells (Yermolaieva et al, 2004) and cardiac myocytes (Prentice et al, 2007) and in MsrA knockout mice elevated levels of brain pathologies have been observed (Pal et al, 2007), possibly due to an accumulation of oxidatively modified proteins that would otherwise have been efficiently repaired by MsrA.…”

Section: The Methionine Sulfoxide Reductase Repair Systemmentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

162

141

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Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O 2 -) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (OONO -). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr)

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Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation

Cited by 152 publications

References 44 publications

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

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

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

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