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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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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. |
format | Online Article Text |
id | pubmed-9821943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
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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