Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice

Torben Johann Hausrat (), Philipp C. Janiesch, Petra Breiden, David Lutz, Sabine Hoffmeister-Ullerich, Irm Hermans-Borgmeyer, Antonio Virgilio Failla and Matthias Kneussel ()
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Torben Johann Hausrat: University Medical Center Hamburg-Eppendorf
Philipp C. Janiesch: University Medical Center Hamburg-Eppendorf
Petra Breiden: University Medical Center Hamburg-Eppendorf
David Lutz: University Medical Center Hamburg-Eppendorf
Sabine Hoffmeister-Ullerich: University Medical Center Hamburg-Eppendorf
Irm Hermans-Borgmeyer: University Medical Center Hamburg-Eppendorf
Antonio Virgilio Failla: University Medical Center Hamburg-Eppendorf
Matthias Kneussel: University Medical Center Hamburg-Eppendorf

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Dissociation of hyper-phosphorylated Tau from neuronal microtubules and its pathological aggregates, are hallmarks in the etiology of tauopathies. The Tau-microtubule interface is subject to polyglutamylation, a reversible posttranslational modification, increasing negative charge at tubulin C-terminal tails. Here, we asked whether tubulin polyglutamylation may contribute to Tau pathology in vivo. Since polyglutamylases modify various proteins other than tubulin, we generated a knock-in mouse carrying gene mutations to abolish Tuba4a polyglutamylation in a substrate-specific manner. We found that Tuba4a lacking C-terminal polyglutamylation prevents the binding of Tau and GSK3 kinase to neuronal microtubules, thereby strongly reducing phospho-Tau levels. Notably, crossbreeding of the Tuba4a knock-in mouse with the hTau tauopathy model, expressing a human Tau transgene, reversed hyper-phosphorylation and oligomerization of Tau and normalized microglia activation in brain. Our data highlight tubulin polyglutamylation as a potential therapeutic strategy in fighting tauopathies.

Date: 2022
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DOI: 10.1038/s41467-022-31776-5

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