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

Autor: Hausrat TJ; Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany. torben.hausrat@zmnh.uni-hamburg.de., Janiesch PC; Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany., Breiden P; Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany., Lutz D; Department of Structural Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany.; Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, 44801, Bochum, Germany., Hoffmeister-Ullerich S; Bioanalytics Facility, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany., Hermans-Borgmeyer I; Transgenic Animal Unit, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany., Failla AV; Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251, Hamburg, Germany., Kneussel M; Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251, Hamburg, Germany. matthias.kneussel@zmnh.uni-hamburg.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jul 20; Vol. 13 (1), pp. 4192. Date of Electronic Publication: 2022 Jul 20.
DOI: 10.1038/s41467-022-31776-5
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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