title: Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice.
abstract: The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.
authors.affiliation: Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.affiliation: MP3-Respiration, UMR CNRS 6231, Faculté Saint-Jérôme, Marseille, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Menuet
authors.affiliation: Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Clara
authors.initials: C
authors.lastname: Theunis
authors.affiliation: Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Justin V
authors.initials: JV
authors.lastname: Louis
authors.affiliation: Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.affiliation: Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Hervé
authors.initials: H
authors.lastname: Maurin
authors.affiliation: Groupe RMN-Glycobiologie, CNRS, University de Lille, Villeneuve d'Ascq, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Smet-Nocca
authors.affiliation: Groupe RMN-Glycobiologie, CNRS, University de Lille, Villeneuve d'Ascq, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.affiliation: MP3-Respiration, UMR CNRS 6231, Faculté Saint-Jérôme, Marseille, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Hilaire
authors.affiliation: Department Neuroscience, Janssen Research & Development, Beerse, Belgium.
authors.forename: Harrie
authors.initials: H
authors.lastname: Gijsen
authors.affiliation: Department Neuroscience, Janssen Research & Development, Beerse, Belgium.
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.affiliation: Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010991:Plethysmography; D011714:Pyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D024801:Tauopathies / Q000188:drug therapy* / Q000503:physiopathology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*; D016875:tau Proteins / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D011714:Pyrans; D013844:Thiazoles; D016875:tau Proteins; C572247:thiamet G; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases