title: Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice.
abstract: Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn protein (i.e. Wrn null mice) do not exhibit a premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum cytokines and markers of cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory cytokine IL-10 and the pro-inflammatory cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum hydroxyproline and plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn protein are mediated by the dysfunction of several cellular organelles.
authors.affiliation: Centre de Recherche du CHU de Québec, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Aumailley
authors.affiliation: Centre de Recherche du CHU de Québec, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Garand
authors.affiliation: Quebec Heart and Lung Institute, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Marie Julie
authors.initials: MJ
authors.lastname: Dubois
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
authors.affiliation: Quebec Heart and Lung Institute, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.affiliation: Centre de Recherche du CHU de Québec, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Lebel
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D018384:Oxidative Stress; D010641:Phenotype; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics*; D014898:Werner Syndrome / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D000071657:Werner Syndrome Helicase
chemical_list: D017382:Reactive Oxygen Species; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse