title: O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases.
abstract: O-GlcNAcylation is an abundant posttranslational modification in the brain implicated in human neurodegenerative diseases. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized Caenorhabditis elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the phenotype in transgenic models of tauopathy, amyloid β-peptide, and polyglutamine expansion. Intriguingly, loss of function of O-GlcNAc transferase alleviated, whereas loss of O-GlcNAcase enhanced, the phenotype of multiple neurodegenerative disease models. The O-GlcNAc cycling mutants act in part by altering DAF-16-dependent transcription and modulating the protein degradation machinery. These findings suggest that O-GlcNAc levels may directly influence neurodegenerative disease progression, thus making the enzymes of O-GlcNAc cycling attractive targets for neurodegenerative disease therapies.
authors.affiliation: Laboratories of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Brooke D
authors.initials: BD
authors.lastname: Lazarus
authors.forename: Michele E
authors.initials: ME
authors.lastname: Forsythe
authors.forename: Dona C
authors.initials: DC
authors.lastname: Love
authors.forename: Michael W
authors.initials: MW
authors.lastname: Krause
authors.forename: John A
authors.initials: JA
authors.lastname: Hanover
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D059748:Proteolysis
chemical_list: D000117:Acetylglucosamine