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Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system

Paulino Ramirez, Wenyan Sun, Gabrielle Zuniga, Elizabeth Ochoa Thomas, Sarah L. DeVos, View ORCID ProfileBradley Hyman, Gabriel Chiu, Ethan R. Roy, Wei Cao, View ORCID ProfileMiranda Orr, View ORCID ProfileVirginie Buggia-Prevot, William J. Ray, View ORCID ProfileBess Frost
doi: https://doi.org/10.1101/2021.02.25.432716
Paulino Ramirez
1Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, Texas
3Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
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Wenyan Sun
1Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, Texas
3Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
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Gabrielle Zuniga
1Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, Texas
3Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
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Elizabeth Ochoa Thomas
1Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, Texas
3Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
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Sarah L. DeVos
4Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
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Bradley Hyman
4Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
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Gabriel Chiu
5Huffington Center on Aging, Baylor College of Medicine, Houston, TX
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Ethan R. Roy
5Huffington Center on Aging, Baylor College of Medicine, Houston, TX
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Wei Cao
5Huffington Center on Aging, Baylor College of Medicine, Houston, TX
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Miranda Orr
6Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC
7WG Hefner VA Medical Center, Salisbury, NC
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  • ORCID record for Miranda Orr
Virginie Buggia-Prevot
8The Neurodegeneration Consortium, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX
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  • ORCID record for Virginie Buggia-Prevot
William J. Ray
8The Neurodegeneration Consortium, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX
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Bess Frost
1Barshop Institute for Longevity and Aging Studies, San Antonio, Texas
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, Texas
3Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, Texas
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  • ORCID record for Bess Frost
  • For correspondence: bfrost@uthscsa.edu
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ABSTRACT

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer disease and related tauopathies, and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class of retrotransposons is particularly enriched. We show that protein encoded by Intracisternal A-particle, a highly active mouse ERV, is elevated in brains of tau transgenic mice. We further demonstrate that brains of tau transgenic mice contain increased DNA copy number of transposable elements, raising the possibility that these elements actively retrotranspose in the context of tauopathy. Taken together, our study lays the groundwork for future mechanistic studies focused on transposable element regulation in the aging mouse brain and in mouse models of tauopathy, while providing support for therapeutic approaches targeting transposable element activation for Alzheimer disease and related tauopathies.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 26, 2021.
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Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system
Paulino Ramirez, Wenyan Sun, Gabrielle Zuniga, Elizabeth Ochoa Thomas, Sarah L. DeVos, Bradley Hyman, Gabriel Chiu, Ethan R. Roy, Wei Cao, Miranda Orr, Virginie Buggia-Prevot, William J. Ray, Bess Frost
bioRxiv 2021.02.25.432716; doi: https://doi.org/10.1101/2021.02.25.432716
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Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system
Paulino Ramirez, Wenyan Sun, Gabrielle Zuniga, Elizabeth Ochoa Thomas, Sarah L. DeVos, Bradley Hyman, Gabriel Chiu, Ethan R. Roy, Wei Cao, Miranda Orr, Virginie Buggia-Prevot, William J. Ray, Bess Frost
bioRxiv 2021.02.25.432716; doi: https://doi.org/10.1101/2021.02.25.432716

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