The Functions of the Mammalian Methionine Sulfoxide Reductase System and Related Diseases

This work is licensed under a Creative Commons Attribution 4.0 International License.This review article describes and discusses the current knowledge on the general role of the methionine sulfoxide reductase (MSR) system and the particular role of MSR type A (MSRA) in mammals. A powerful tool to investigate the contribution of MSRA to molecular processes within a mammalian system/organism is the MSRA knockout. The deficiency of MSRA in this mouse model provides hints and evidence for this enzyme function in health and disease. Accordingly, the potential involvement of MSRA in the processes leading to neurodegenerative diseases, neurological disorders, cystic fibrosis, cancer, and hearing loss will be deliberated and evaluated.Hedwig Miller Fund for Aging Researc

Selenium and the Methionine Sulfoxide Reductase System

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution licenseSelenium is a chemical element participating in the synthesis of selenocysteine residues that play a pivotal role in the enzymatic activity efficiency of selenoproteines. The methionine sulfoxide reductase (Msr) system that reduces methionine sulfoxide (MetO) to methionine comprises the selenoprotein MsrB (MsrB1) and the non-selenoprotein MsrA, which reduce the R- and the S- forms of MetO, respectively. The effects of a selenium deficient (SD) diet, which was administrated to wild type (WT) and MsrA knockout mice (MsrA-/-), on the expression and function of Msr-related proteins are examined and discussed. Additionally, new data about the levels of selenium in brain, liver, and kidneys of WT and MsrA-/- mice are presented and discussed

Decreased Phosphorylation and Increased Methionine Oxidation of α-Synuclein in the Methionine Sulfoxide Reductase A Knockout Mouse

Previously, we have showed that overexpression of methionine-oxidized α-synuclein in methionine sulfoxide reductase A (MsrA) null mutant yeast cells inhibits α-synuclein phosphorylation and increases protein fibrillation. The current studies show that ablation of mouse MsrA gene caused enhanced methionine oxidation of α-synuclein while reducing its own phophorylation levels, especially in the hydrophobic cell-extracted fraction. These data provide supportive evidence that a compromised MsrA function in mammalian brain may cause enhanced pathologies associated with altered α-synuclein oxidation and phosphorylation levels

Clearance and Phosphorylation of Alpha-Synuclein Are Inhibited in Methionine Sulfoxide Reductase A Null Yeast Cells

Aggregated α-synuclein and the point mutations Ala30Pro and Ala53Thr of α-synuclein are associated with Parkinson’s disease. The physiological roles of α-synuclein and methionine oxidation of the α-synuclein protein structure and function are not fully understood. Methionine sulfoxide reductase A (MsrA) reduces methionine sulfoxide residues and functions as an antioxidant. To monitor the effect of methionine oxidation to α-synuclein on basic cellular processes, α-synucleins were expressed in msrA null mutant and wild-type yeast cells. Protein degradation was inhibited in the α-synuclein-expressing msrA null mutant cells compared to α-synuclein-expressing wild-type cells. Increased inhibition of degradation and elevated accumulations of fibrillated proteins were observed in SynA30P-expressing msrA null mutant cells. Additionally, methionine oxidation inhibited α-synuclein phosphorylation in yeast cells and in vitro by casein kinase 2. Thus, a compromised MsrA function combined with α-synuclein overexpression may promote processes leading to synucleinopathies

Physical map location of the peptide methionine sulfoxide reductase gene on the Escherichia coli chromosome

This is the publisher's version, also available electronically from "http://jb.asm.org".No abstract available

Quantification of Reserve Pool Dopamine in Methionine Sulfoxide Reductase A Null Mice

Methionine sulfoxide reductase A knockout (MsrA−/−) mice, which serve as a potential model for neurodegeneration, suffer from increased oxidative stress and have previously been found to have chronically elevated brain dopamine content levels relative to control mice. Additionally, these high levels parallel increased presynaptic dopamine release. In this work, fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used to quantify striatal reserve pool dopamine in knockout mice and wild-type control mice. Reserve pool dopamine efflux, induced by amphetamine, was measured in brain slices from knockout and wild type mice in the presence of α-methyl-p-tyrosine, a dopamine synthesis inhibitor. Additionally, the stimulated release of reserve pool dopamine, mobilized by cocaine, was measured. Both efflux and stimulated release measurements were enhanced in slices from knockout mice, suggesting that these mice have greater reserve pool dopamine stores than wild-type and that these stores are effectively mobilized. Moreover, dopamine transporter labeling data indicate that the difference in measured dopamine efflux was likely not caused by altered dopamine transporter protein expression. Additionally, slices from MsrA−/− and wild-type mice were equally responsive to increasing extracellular calcium concentrations, suggesting that potential differences in either calcium entry or intracellular calcium handling are not responsible for increased reserve pool dopamine release. Collectively, these results demonstrate that MsrA−/− knockout mice maintain a larger dopamine reserve pool than wild-type control mice, and that this pool is readily mobilized

The Antioxidant Enzyme Methionine Sulfoxide Reductase A (MsrA) Interacts with Jab1/CSN5 and Regulates Its Function

This work is licensed under a Creative Commons Attribution 4.0 International License.Methionine sulfoxide (MetO) is an oxidative posttranslational modification that primarily occurs under oxidative stress conditions, leading to alteration of protein structure and function. This modification is regulated by MetO reduction through the evolutionarily conserved methionine sulfoxide reductase (Msr) system. The Msr type A enzyme (MsrA) plays an important role as a cellular antioxidant and promotes cell survival. The ubiquitin- (Ub) like neddylation pathway, which is controlled by the c-Jun activation domain-binding protein-1 (Jab1), also affects cell survival. Jab1 negatively regulates expression of the cell cycle inhibitor cyclin-dependent kinase inhibitor 1B (P27) through binding and targeting P27 for ubiquitination and degradation. Here we report the finding that MsrA interacts with Jab1 and enhances Jab1′s deneddylase activity (removal of Nedd8). In turn, an increase is observed in the level of deneddylated Cullin-1 (Cul-1, a component of E3 Ub ligase complexes). Furthermore, the action of MsrA increases the binding affinity of Jab1 to P27, while MsrA ablation causes a dramatic increase in P27 expression. Thus, an interaction between MsrA and Jab1 is proposed to have a positive effect on the function of Jab1 and to serve as a means to regulate cellular resistance to oxidative stress and to enhance cell survival.Hedwig Miller Fund for Aging Research of the University of KansasU.S. Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences, Physical Biosciences Program (DOE DE-FG02-05ER15650)NIH R01 GM5749

Methionine sulfoxide reductase regulates brain catechol-O-methyl transferase activity

This is the published version. Copyright 2014 Oxford University PressCatechol-O-methyl transferase (COMT) plays a key role in the degradation of brain dopamine (DA). Specifically, low COMT activity results in higher DA levels in the prefrontal cortex (PFC), thereby reducing the vulnerability for attentional and cognitive deficits in both psychotic and healthy individuals. COMT activity is markedly reduced by a non-synonymous single-nucleotide polymorphism (SNP) that generates a valine-to-methionine substitution on the residue 108/158, by means of as-yet incompletely understood post-translational mechanisms. One post-translational modification is methionine sulfoxide, which can be reduced by the methionine sulfoxide reductase (Msr) A and B enzymes. We used recombinant COMT proteins (Val/Met108) and mice (wild-type (WT) and MsrA knockout) to determine the effect of methionine oxidation on COMT activity and COMT interaction with Msr, through a combination of enzymatic activity and Western blot assays. Recombinant COMT activity is positively regulated by MsrA, especially under oxidative conditions, whereas brains of MsrA knockout mice exhibited lower COMT activity (as compared with their WT counterparts). These results suggest that COMT activity may be reduced by methionine oxidation, and point to Msr as a key molecular determinant for the modulation of COMT activity in the brain. The role of Msr in modulating cognitive functions in healthy individuals and schizophrenia patients is yet to be determined

Caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse

Oxidative stress is associated with the aging process, a risk factor for neurodegenerative diseases, and decreased by reduced energy intake. Oxidative modifications can affect protein function; the sulfur-containing amino acids, including methionine, are particularly susceptible to oxidation. A methionine sulfoxide can be enzymatically reduced by the methionine sulfoxide reductase (Msr) system. Previously, we have shown that MsrA−/− mice exhibit altered locomotor activity and brain dopamine levels as function of age. Previous studies have demonstrated that a caloric restriction enhances antioxidant defense and reduces the action of reactive oxygen species. Here we examine locomotor behavior and dopamine levels of MsrA−/− mice after caloric restriction starting at 8 months of age and ending at 17 months. The MsrA−/− mice did not have any significant difference in spontaneous distance traveled when compared to controls at 17 months of age. In contrast, our previous report showed decreased locomotor activity in the MsrA−/− mice at 12 months of age and older when fed ad-libitum. After completion of the caloric restriction diet, dopamine levels were comparable to control mice. This differs from the abnormal dopamine levels previously observed in MsrA−/− mice fed ad-libitum. Thus, caloric restriction had a neutralization effect on MsrA ablation. In summary, it is suggested that caloric restriction alleviates abnormal locomotor activity and dopamine levels in the brain of the methionine sulfoxide reductase A knockout mouse

The enzymatic activities of brain COMT and methionine sulfoxide reductase are correlated in a COMT Val/Met allele-dependent fashion

This is the peer reviewed version of the following article: J. Moskovitz, C. Walss-Bass, D. A. Cruz, P. M. Thompson, J. Hairston and M. Bortolato (2015) Neuropathology and Applied Neurobiology The enzymatic activities of brain catechol-O-methyltransferase (COMT) and methionine sulphoxide reductase are correlated in a COMT Val/Met allele-dependent fashion, which has been published in final form at http://doi.org/10.1111/nan.12219. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.AIMS: The enzyme catechol-O-methyl transferase (COMT) plays a primary role in the metabolism of catecholamine neurotransmitters and is implicated in the modulation of cognitive and emotional responses. The best-characterized single nucleotide polymorphism (SNP) of the COMT gene consists of a valine (Val)-to-methionine (Met) substitution at codon 108/158. The Met-containing variant confers a marked reduction in COMT catalytic activity. We recently showed that the activity of recombinant COMT is positively regulated by the enzyme Met sulfoxide reductase (MSR), which counters the oxidation of Met residues of proteins. The current study was designed to assess whether brain COMT activity may be correlated to MSR in an allele-dependent fashion. METHODS: COMT and MSR activities were measured from post-mortem samples of prefrontal cortices, striata and cerebella of 32 subjects, by using catechol and dabsyl-Met sulfoxide as substrates, respectively. Allelic discrimination of COMT Val108/185Met SNP was performed using the Taqman 5’nuclease assay. RESULTS: Our studies revealed that, in homozygous carriers of Met, but not Val alleles, the activity of COMT and MSR were significantly correlated throughout all tested brain regions. DISCUSSION: These results suggest that the reduced enzymatic activity of Met-containing COMT may be secondary to Met sulfoxidation, and point to MSR as a key molecular determinant for the modulation of COMT activity