Elevated levels of brain-pathologies associated with neurodegenerative diseases in the methionine sulfoxide reductase A knockout mouse.
One of the posttranslational modifications to proteins is methionine oxidation, which is readily reversible by the methionine sulfoxide reductase (Msr) system. Thus, accumulation of faulty proteins due to a compromised Msr system may lead to the development of aging-associated diseases like neurodegenerative diseases. In particular, it was interesting to monitor the consequential effects of methionine oxidation in relation to markers that are associated with Alzheimer's disease as methionine oxidation was implied to play a role in beta-amyloid toxicity. In this study, a knockout mouse strain of the methionine sulfoxide reductase A gene (MsrA ( -/- )) caused an enhanced neurodegeneration in brain hippocampus relative to its wild-type control mouse brain. Additionally, a loss of astrocytes integrity, elevated levels of beta-amyloid deposition, and tau phosphorylation were dominant in various regions of the MsrA ( -/- ) hippocampus but not in the wild-type. Also, a comparison between cultured brain slices of the hippocampal region of both mouse strains showed more sensitivity of the MsrA ( -/- ) cultured cells to H(2)O(2) treatment. It is suggested that a deficiency in MsrA activity fosters oxidative-stress that is manifested by the accumulation of faulty proteins (via methionine oxidation), deposition of aggregated proteins, and premature brain cell death.
Pal
Ranu
R
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.
Oien
Derek B
DB
Ersen
Fatma Y
FY
Moskovitz
Jackob
J
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005609:Free Radicals / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000633:toxicity; D008715:Methionine / Q000378:metabolism*; D051150:Methionine Sulfoxide Reductases; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics*; D017510:Protein Folding; D013045:Species Specificity; D016708:Synaptophysin / Q000032:analysis / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D005904:Glial Fibrillary Acidic Protein; D016708:Synaptophysin; D016875:tau Proteins; D008715:Methionine; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase