Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice

Ikezu, Tsuneya and Borghgraef, Peter and Menuet, Clément and Theunis, Clara and Louis, Justin V. and Devijver, Herman and Maurin, Hervé and Smet-Nocca, Caroline and Lippens, Guy and Hilaire, Gerard and Gijsen, Harrie and Moechars, Dieder and Van Leuven, Fred (2013) Increasing Brain Protein O-GlcNAc-ylation Mitigates Breathing Defects and Mortality of Tau.P301L Mice. PLoS ONE, 8 (12). pp. 1-13. ISSN 1932-6203

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Official URL: http://dx.doi.org/10.1371/journal.pone.0084442

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 prefixed 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 upperairway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAcase. 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.

Item Type: Article
Subjects: Pharmaceutical Sciences
Divisions: College of Pharmacy > Pharmaceutical Sciences
Depositing User: Dr Justin Louis
Date Deposited: 31 May 2017 10:54
Last Modified: 31 May 2017 10:54
URI: http://eprints.kku.edu.sa/id/eprint/756

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