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

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Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice. / Hausrat, Torben Johann; Janiesch, Philipp C; Breiden, Petra; Lutz, David; Hoffmeister-Ullerich, Sabine; Hermans-Borgmeyer, Irm; Failla, Antonio Virgilio; Kneussel, Matthias.

In: NAT COMMUN, Vol. 13, No. 1, 4192, 20.07.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Hausrat, TJ, Janiesch, PC, Breiden, P, Lutz, D, Hoffmeister-Ullerich, S, Hermans-Borgmeyer, I, Failla, AV & Kneussel, M 2022, 'Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice', NAT COMMUN, vol. 13, no. 1, 4192. https://doi.org/10.1038/s41467-022-31776-5

APA

Hausrat, T. J., Janiesch, P. C., Breiden, P., Lutz, D., Hoffmeister-Ullerich, S., Hermans-Borgmeyer, I., Failla, A. V., & Kneussel, M. (2022). Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice. NAT COMMUN, 13(1), [4192]. https://doi.org/10.1038/s41467-022-31776-5

Vancouver

Hausrat TJ, Janiesch PC, Breiden P, Lutz D, Hoffmeister-Ullerich S, Hermans-Borgmeyer I et al. Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice. NAT COMMUN. 2022 Jul 20;13(1). 4192. https://doi.org/10.1038/s41467-022-31776-5

Bibtex

@article{910c4f25a36447b0a2e27ffad9d64136,
title = "Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice",
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.",
keywords = "Animals, Glycogen Synthase Kinase 3/metabolism, Humans, Mice, Microglia/metabolism, Microtubules/metabolism, Phosphorylation, Tauopathies/metabolism, Tubulin/genetics, tau Proteins/genetics",
author = "Hausrat, {Torben Johann} and Janiesch, {Philipp C} and Petra Breiden and David Lutz and Sabine Hoffmeister-Ullerich and Irm Hermans-Borgmeyer and Failla, {Antonio Virgilio} and Matthias Kneussel",
note = "{\textcopyright} 2022. The Author(s).",
year = "2022",
month = jul,
day = "20",
doi = "10.1038/s41467-022-31776-5",
language = "English",
volume = "13",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Disruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice

AU - Hausrat, Torben Johann

AU - Janiesch, Philipp C

AU - Breiden, Petra

AU - Lutz, David

AU - Hoffmeister-Ullerich, Sabine

AU - Hermans-Borgmeyer, Irm

AU - Failla, Antonio Virgilio

AU - Kneussel, Matthias

N1 - © 2022. The Author(s).

PY - 2022/7/20

Y1 - 2022/7/20

N2 - 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.

AB - 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.

KW - Animals

KW - Glycogen Synthase Kinase 3/metabolism

KW - Humans

KW - Mice

KW - Microglia/metabolism

KW - Microtubules/metabolism

KW - Phosphorylation

KW - Tauopathies/metabolism

KW - Tubulin/genetics

KW - tau Proteins/genetics

U2 - 10.1038/s41467-022-31776-5

DO - 10.1038/s41467-022-31776-5

M3 - SCORING: Journal article

C2 - 35858909

VL - 13

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

M1 - 4192

ER -