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Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice
Peter Borghgraef1, Clément Menuet2, Clara Theunis1
1Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
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.
Insights
Inhibiting O-GlcNAc-ase benefited Tau.P301L mice, improving motor function and survival. This neuroprotection occurred downstream of direct tau protein modification.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Tau protein pathology drives tauopathies, including neurodegeneration.
- The precise molecular mechanisms underlying tauopathies remain largely unknown.
- Post-translational protein modification, specifically O-GlcNAc-ylation, is increasingly recognized for its cellular roles.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting O-GlcNAc-ase in a mouse model of tauopathy.
- To determine if O-GlcNAc-ylation of brain proteins impacts the progression of tauopathy.
- To explore the direct biochemical interaction between O-GlcNAc-ylation and the tau protein.
Main Methods:
- Pharmacological inhibition of O-GlcNAc-ase in aging Tau.P301L mice.
- Assessment of body weight, motor function, survival rates, and respiratory parameters.
- Biochemical analysis to measure O-GlcNAc-ylation levels and tau protein phosphorylation.
Main Results:
- Chronic O-GlcNAc-ase inhibition significantly improved body weight, motor deficits, and breathing in Tau.P301L mice.
- Survival of treated mice was threefold higher compared to controls at the study endpoint.
- Increased O-GlcNAc-ylation of brain proteins was observed, but direct O-GlcNAc-ylation or altered phosphorylation of tau protein was not detected.
Conclusions:
- Pharmacological O-GlcNAc-ase inhibition offers a promising therapeutic strategy for tauopathies.
- The beneficial effects appear to act downstream of direct tau modification, suggesting a broader impact on the pathological cascade.
- This approach opens new avenues for understanding and treating tau-mediated neurodegeneration.
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