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Pathogenic tau disrupts the cellular program that maintains neuronal identity

View ORCID ProfileAdrian Beckmann, View ORCID ProfilePaulino Ramirez, Maria Gamez, View ORCID ProfileWilliam J. Ray, View ORCID ProfileBess Frost
doi: https://doi.org/10.1101/2021.03.05.434166
Adrian Beckmann
1Barshop Institute for Longevity and Aging Studies, University of Texas MD Anderson Cancer Center, Houston TX
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas MD Anderson Cancer Center, Houston TX
3Department of Cell Systems and Anatomy, University of Texas MD Anderson Cancer Center, Houston TX
4University of Texas Health San Antonio, San Antonio, TX, University of Texas MD Anderson Cancer Center, Houston TX
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  • ORCID record for Adrian Beckmann
Paulino Ramirez
1Barshop Institute for Longevity and Aging Studies, University of Texas MD Anderson Cancer Center, Houston TX
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas MD Anderson Cancer Center, Houston TX
3Department of Cell Systems and Anatomy, University of Texas MD Anderson Cancer Center, Houston TX
4University of Texas Health San Antonio, San Antonio, TX, University of Texas MD Anderson Cancer Center, Houston TX
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Maria Gamez
1Barshop Institute for Longevity and Aging Studies, University of Texas MD Anderson Cancer Center, Houston TX
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas MD Anderson Cancer Center, Houston TX
3Department of Cell Systems and Anatomy, University of Texas MD Anderson Cancer Center, Houston TX
4University of Texas Health San Antonio, San Antonio, TX, University of Texas MD Anderson Cancer Center, Houston TX
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William J. Ray
5The 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, University of Texas MD Anderson Cancer Center, Houston TX
2Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas MD Anderson Cancer Center, Houston TX
3Department of Cell Systems and Anatomy, University of Texas MD Anderson Cancer Center, Houston TX
4University of Texas Health San Antonio, San Antonio, TX, University of Texas MD Anderson Cancer Center, Houston TX
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  • For correspondence: bfrost@uthscsa.edu
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Abstract

Neurons in human Alzheimer’s disease acquire phenotypes that are also present in various cancers, including over-stabilization of the cytoskeleton, nuclear pleomorphism, decondensation of constitutive heterochromatin, and aberrant activation of the cell cycle. Unlike in cancer, in which cell cycle activation drives tumor formation, activation of the cell cycle in post-mitotic neurons is sufficient to induce neuronal death. Multiple lines of evidence suggest that abortive cell cycle activation is a consequence of pathogenic forms of tau, a protein that drives neurodegeneration in Alzheimer’s disease and related “tauopathies.” We have combined network analysis of human Alzheimer’s disease and mouse tauopathy with mechanistic studies in Drosophila to discover that pathogenic forms of tau drive abortive cell cycle activation by disrupting the cellular program that maintains neuronal identity. Mechanistically, we identify Moesin, a prognostic biomarker for cancer and mediator of the epithelial-mesenchymal transition (EMT), as a major effector of tau-induced neurotoxicity. We find that aberrant activation of Moesin in neurons acts through the actin cytoskeleton to dysregulate the cellular program that maintains neuronal identity. Our study identifies mechanistic parallels between tauopathy and cancer and sets the stage for novel therapeutic approaches.

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. All rights reserved. No reuse allowed without permission.
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Posted March 07, 2021.
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Pathogenic tau disrupts the cellular program that maintains neuronal identity
Adrian Beckmann, Paulino Ramirez, Maria Gamez, William J. Ray, Bess Frost
bioRxiv 2021.03.05.434166; doi: https://doi.org/10.1101/2021.03.05.434166
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Pathogenic tau disrupts the cellular program that maintains neuronal identity
Adrian Beckmann, Paulino Ramirez, Maria Gamez, William J. Ray, Bess Frost
bioRxiv 2021.03.05.434166; doi: https://doi.org/10.1101/2021.03.05.434166

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