Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice

• Published in: PloS one Vol. 8; no. 12; p. e84442
• Main Authors: Borghgraef, Peter, Menuet, Clément, Theunis, Clara, Louis, Justin V, Devijver, Herman, Maurin, Hervé, Smet-Nocca, Caroline, Lippens, Guy, Hilaire, Gerard, Gijsen, Harrie, Moechars, Dieder, Van Leuven, Fred
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.12.2013; Public Library of Science (PLoS)
• Subjects: Aging; Alzheimer's disease; Alzheimers disease; Analysis of Variance; Animals; beta-N-Acetylhexosaminidases - antagonists & inhibitors; Biochemistry; Biochemistry, Molecular Biology; Blotting, Western; Brain; Brain - metabolism; Brain research; Breathing; Defects; Digital music; Female; Genetics; Health aspects; Immunohistochemistry; Immunoprecipitation; Inhibition; Kinases; Life Sciences; Mice; Mice, Transgenic; Molecular modelling; Mortality; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Pharmacology; Phosphorylation; Physiology; Plethysmography; Post-translation; Proteins; Pyrans - chemical synthesis; Pyrans - pharmacology; R&D; Research & development; Respiration; Respiratory Mechanics - drug effects; Respiratory Mechanics - physiology; Respiratory tract; Rodents; Survival; Tau protein; tau Proteins - genetics; Tauopathies - drug therapy; Tauopathies - physiopathology; Thiazoles - chemical synthesis; Thiazoles - pharmacology; Transgenic animals; Belgium
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084442

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.