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

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Derek B. Oien ◽  
Gonzalo A. Carrasco ◽  
Jackob Moskovitz
Keyword(s):  
Knockout Mouse ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Yeast Cells ◽  
Mammalian Brain ◽  
Methionine Oxidation ◽  
Null Mutant ◽  
Supportive Evidence ◽  
Methionine Sulfoxide Reductase A ◽  
Protein Fibrillation

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.

Abstract 524: Deletion of Methionine Sulfoxide Reductase A in Mice Increases Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Paula J Klutho ◽  
Jason Scott ◽  
Litao Xie ◽  
Isabella M Grumbach
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Neointimal Hyperplasia ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Oxidation ◽  
Cyclin D ◽  
Mrna Levels ◽  
Neointima Formation ◽  
Methionine Sulfoxide Reductase A

Introduction: Neointima formation is the leading cause of restenosis after balloon angioplasty and surgical endarterectomy. ROS production promotes neointimal hyperplasia and causes methionine oxidation. Recent data suggest that oxidation of methionines can alter specific protein activity and induce cell signaling. Methionine Sulfoxide Reductase A (MsrA) reverses methionine oxidation. In humans, two independent genome-wide association studies have found MsrA polymorphisms to correlate with increased ischemic cardiovascular disease. Hypothesis: MsrA protects against neointimal formation. Methods: Immunofluorescence for MsrA was performed in autopsy specimen of arteries with and without neointimal hyperplasia. 12-week old WT and MsrA-/- mice underwent ligation of the left common carotid artery and received two injections of BrdU prior to sacrifice. Fourteen days after ligation, the neointimal area was determined using Image J. Cell proliferation and apoptosis in the neointima were quantified by BrdU and TUNEL staining. Proliferation of vascular smooth muscle cells (VSMC) from MsrA-/- and WT mice was determined by cell counts and FACS analysis. Levels of cell cycle proteins, pAkt, pGSK3β were analyzed by immunoblot in MsrA-/- and WT VSMC, mRNA levels by qrtPCR. Results: MsrA was detected in all layers of the vascular wall and in neointima in humans. Neointimal area was significantly increased in MsrA-/- compared to WT mice 14 days post-ligation (n=5-9, p<0.05). Additionally, neointimas from MsrA-/- mice contained a higher percentage of proliferating cells (0.92±1.42% vs 8.89±8.89%, p=0.007). MsrA-/- VSMC displayed significantly increased proliferation compared to WT VSMC (p<0.05). Moreover, the progression to S phase was accelerated and protein levels of the cell cycle regulators Cyclin D and CDK4 were upregulated in MsrA-/- VSMC. However, cyclin D mRNA levels are not increased (p=0.24). This implies that MsrA post-translationally regulates cyclin D. GSK3β, which is inhibited by Akt, promotes cyclin D degradation. An increase in pAkt and pGSK3β was identified in MsrA-/- VSMC. Conclusion: These data indicate that MsrA regulates neointima formation after vascular injury and support a role for MsrA in the regulation of Akt signaling.

scholarly journals The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1372
Author(s):  
Tengrui Shi ◽  
Jianxi Song ◽  
Guanying You ◽  
Yujie Yang ◽  
Qiong Liu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Methionine Sulfoxide ◽  
Methionine Sulfoxide Reductase ◽  
Knockout Mouse Model ◽  
The Central Nervous System

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

scholarly journals An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii

2021 ◽  
Vol 78 (7) ◽  
pp. 3673-3689
Author(s):  
David Leitsch ◽  
Alvie Loufouma Mbouaka ◽  
Martina Köhsler ◽  
Norbert Müller ◽  
Julia Walochnik
Keyword(s):  
Oxidative Stress ◽  
Stop Codon ◽  
Acanthamoeba Castellanii ◽  
Methionine Sulfoxide ◽  
Redox System ◽  
Methionine Sulfoxide Reductase ◽  
Methionine Sulfoxide Reductase A ◽  
Protein Levels ◽  
Thioredoxin System ◽  
Facultative Parasite

AbstractThe free-living amoeba Acanthamoeba castellanii occurs worldwide in soil and water and feeds on bacteria and other microorganisms. It is, however, also a facultative parasite and can cause serious infections in humans. The annotated genome of A. castellanii (strain Neff) suggests the presence of two different thioredoxin reductases (TrxR), of which one is of the small bacterial type and the other of the large vertebrate type. This combination is highly unusual. Similar to vertebrate TrxRases, the gene coding for the large TrxR in A. castellanii contains a UGA stop codon at the C-terminal active site, suggesting the presence of selenocysteine. We characterized the thioredoxin system in A. castellanii in conjunction with glutathione reductase (GR), to obtain a more complete understanding of the redox system in A. castellanii and the roles of its components in the response to oxidative stress. Both TrxRases localize to the cytoplasm, whereas GR localizes to the cytoplasm and the large organelle fraction. We could only identify one thioredoxin (Trx-1) to be indeed reduced by one of the TrxRases, i.e., by the small TrxR. This thioredoxin, in turn, could reduce one of the two peroxiredoxins tested and also methionine sulfoxide reductase A (MsrA). Upon exposure to hydrogen peroxide and diamide, only the small TrxR was upregulated in expression at the mRNA and protein levels, but not the large TrxR. Our results show that the small TrxR is involved in the A. castellanii’s response to oxidative stress. The role of the large TrxR, however, remains elusive.

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