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Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation

Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of “tauopathies,” including Alzheimer’s disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, ide...

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Autores principales: Ochoa, Elizabeth, Ramirez, Paulino, Gonzalez, Elias, De Mange, Jasmine, Ray, William J., Bieniek, Kevin F., Frost, Bess
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821943/
https://www.ncbi.nlm.nih.gov/pubmed/36608133
http://dx.doi.org/10.1126/sciadv.abq5423
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author Ochoa, Elizabeth
Ramirez, Paulino
Gonzalez, Elias
De Mange, Jasmine
Ray, William J.
Bieniek, Kevin F.
Frost, Bess
author_facet Ochoa, Elizabeth
Ramirez, Paulino
Gonzalez, Elias
De Mange, Jasmine
Ray, William J.
Bieniek, Kevin F.
Frost, Bess
author_sort Ochoa, Elizabeth
collection PubMed
description Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of “tauopathies,” including Alzheimer’s disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau–induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA). We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau–induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element–derived dsRNA in the adult brain.
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spelling pubmed-98219432023-01-18 Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation Ochoa, Elizabeth Ramirez, Paulino Gonzalez, Elias De Mange, Jasmine Ray, William J. Bieniek, Kevin F. Frost, Bess Sci Adv Neuroscience Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of “tauopathies,” including Alzheimer’s disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau–induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA). We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau–induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element–derived dsRNA in the adult brain. American Association for the Advancement of Science 2023-01-06 /pmc/articles/PMC9821943/ /pubmed/36608133 http://dx.doi.org/10.1126/sciadv.abq5423 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Neuroscience
Ochoa, Elizabeth
Ramirez, Paulino
Gonzalez, Elias
De Mange, Jasmine
Ray, William J.
Bieniek, Kevin F.
Frost, Bess
Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
title Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
title_full Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
title_fullStr Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
title_full_unstemmed Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
title_short Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
title_sort pathogenic tau–induced transposable element–derived dsrna drives neuroinflammation
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821943/
https://www.ncbi.nlm.nih.gov/pubmed/36608133
http://dx.doi.org/10.1126/sciadv.abq5423
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