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Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

Xinyu Xiang, Tamta Arakhamia, Yari Carlomagno, Shikhar Dhingra, Manon Thierry, Michael DeTure, Casey N. Cook, Dennis W. Dickson, Leonard Petrucelli, Anthony W. P. Fitzpatrick
doi: https://doi.org/10.1101/2021.05.24.445353
Xinyu Xiang
1Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
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Tamta Arakhamia
1Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
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Yari Carlomagno
4Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
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Shikhar Dhingra
1Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
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Manon Thierry
1Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
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Michael DeTure
4Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
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Casey N. Cook
4Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
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Dennis W. Dickson
4Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
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Leonard Petrucelli
4Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
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Anthony W. P. Fitzpatrick
1Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
3Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, USA
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  • For correspondence: Anthony.Fitzpatrick@columbia.edu
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Abstract

Misfolding and aggregation of tau protein is implicated in many neurodegenerative diseases that are typified by the presence of large, filamentous tau inclusions. The aggregation of tau in human brain is disease-specific with characteristic filaments defining the neuropathology. An understanding of how identical tau isoforms aggregate into disparate filament morphologies in phenotypically distinct tau-related diseases remains elusive. Here, we determine the structure of a brain-derived twisted tau filament in progressive supranuclear palsy and compare it to a dissimilar tau fold found in corticobasal degeneration. While the tau filament core in both diseases is comprised of residues 274 to 380, molecular-level polymorphism exists. Potential origins of the molecular polymorphism, such as noncovalent cofactor binding, are identified and predicted to modulate tau filament structures in the brain.

Competing Interest Statement

The authors have declared no competing interest.

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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 May 25, 2021.
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Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases
Xinyu Xiang, Tamta Arakhamia, Yari Carlomagno, Shikhar Dhingra, Manon Thierry, Michael DeTure, Casey N. Cook, Dennis W. Dickson, Leonard Petrucelli, Anthony W. P. Fitzpatrick
bioRxiv 2021.05.24.445353; doi: https://doi.org/10.1101/2021.05.24.445353
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Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases
Xinyu Xiang, Tamta Arakhamia, Yari Carlomagno, Shikhar Dhingra, Manon Thierry, Michael DeTure, Casey N. Cook, Dennis W. Dickson, Leonard Petrucelli, Anthony W. P. Fitzpatrick
bioRxiv 2021.05.24.445353; doi: https://doi.org/10.1101/2021.05.24.445353

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