Cargando…

Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau

Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the b...

Descripción completa

Detalles Bibliográficos
Autores principales: Schweighauser, Manuel, Murzin, Alexey G., Macdonald, Jennifer, Lavenir, Isabelle, Crowther, R. Anthony, Scheres, Sjors H.W., Goedert, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552433/
https://www.ncbi.nlm.nih.gov/pubmed/37798679
http://dx.doi.org/10.1186/s40478-023-01658-y
_version_ 1785115962155991040
author Schweighauser, Manuel
Murzin, Alexey G.
Macdonald, Jennifer
Lavenir, Isabelle
Crowther, R. Anthony
Scheres, Sjors H.W.
Goedert, Michel
author_facet Schweighauser, Manuel
Murzin, Alexey G.
Macdonald, Jennifer
Lavenir, Isabelle
Crowther, R. Anthony
Scheres, Sjors H.W.
Goedert, Michel
author_sort Schweighauser, Manuel
collection PubMed
description Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01658-y.
format Online
Article
Text
id pubmed-10552433
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-105524332023-10-06 Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau Schweighauser, Manuel Murzin, Alexey G. Macdonald, Jennifer Lavenir, Isabelle Crowther, R. Anthony Scheres, Sjors H.W. Goedert, Michel Acta Neuropathol Commun Research Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-023-01658-y. BioMed Central 2023-10-05 /pmc/articles/PMC10552433/ /pubmed/37798679 http://dx.doi.org/10.1186/s40478-023-01658-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Schweighauser, Manuel
Murzin, Alexey G.
Macdonald, Jennifer
Lavenir, Isabelle
Crowther, R. Anthony
Scheres, Sjors H.W.
Goedert, Michel
Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau
title Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau
title_full Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau
title_fullStr Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau
title_full_unstemmed Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau
title_short Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau
title_sort cryo-em structures of tau filaments from the brains of mice transgenic for human mutant p301s tau
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552433/
https://www.ncbi.nlm.nih.gov/pubmed/37798679
http://dx.doi.org/10.1186/s40478-023-01658-y
work_keys_str_mv AT schweighausermanuel cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau
AT murzinalexeyg cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau
AT macdonaldjennifer cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau
AT lavenirisabelle cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau
AT crowtherranthony cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau
AT scheressjorshw cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau
AT goedertmichel cryoemstructuresoftaufilamentsfromthebrainsofmicetransgenicforhumanmutantp301stau