Cargando…

Pathogenic tau decreases nuclear tension in cultured neurons

Neurodegenerative tauopathies, including Alzheimer’s disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic...

Descripción completa

Detalles Bibliográficos
Autores principales: Sohn, Claira, Ma, Jiacheng, Ray, William J., Frost, Bess
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901542/
https://www.ncbi.nlm.nih.gov/pubmed/36756194
http://dx.doi.org/10.3389/fragi.2023.1058968
_version_ 1784883046281904128
author Sohn, Claira
Ma, Jiacheng
Ray, William J.
Frost, Bess
author_facet Sohn, Claira
Ma, Jiacheng
Ray, William J.
Frost, Bess
author_sort Sohn, Claira
collection PubMed
description Neurodegenerative tauopathies, including Alzheimer’s disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer’s disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.
format Online
Article
Text
id pubmed-9901542
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-99015422023-02-07 Pathogenic tau decreases nuclear tension in cultured neurons Sohn, Claira Ma, Jiacheng Ray, William J. Frost, Bess Front Aging Aging Neurodegenerative tauopathies, including Alzheimer’s disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer’s disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders. Frontiers Media S.A. 2023-01-23 /pmc/articles/PMC9901542/ /pubmed/36756194 http://dx.doi.org/10.3389/fragi.2023.1058968 Text en Copyright © 2023 Sohn, Ma, Ray and Frost. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging
Sohn, Claira
Ma, Jiacheng
Ray, William J.
Frost, Bess
Pathogenic tau decreases nuclear tension in cultured neurons
title Pathogenic tau decreases nuclear tension in cultured neurons
title_full Pathogenic tau decreases nuclear tension in cultured neurons
title_fullStr Pathogenic tau decreases nuclear tension in cultured neurons
title_full_unstemmed Pathogenic tau decreases nuclear tension in cultured neurons
title_short Pathogenic tau decreases nuclear tension in cultured neurons
title_sort pathogenic tau decreases nuclear tension in cultured neurons
topic Aging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901542/
https://www.ncbi.nlm.nih.gov/pubmed/36756194
http://dx.doi.org/10.3389/fragi.2023.1058968
work_keys_str_mv AT sohnclaira pathogenictaudecreasesnucleartensioninculturedneurons
AT majiacheng pathogenictaudecreasesnucleartensioninculturedneurons
AT raywilliamj pathogenictaudecreasesnucleartensioninculturedneurons
AT frostbess pathogenictaudecreasesnucleartensioninculturedneurons