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Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

Tara E. Tracy, View ORCID ProfileJesus Madero-Pérez, View ORCID ProfileDanielle Swaney, View ORCID ProfileTimothy S. Chang, View ORCID ProfileMichelle Moritz, Csaba Konrad, Michael E. Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue-Ann Mok, Maria Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn, Jordie Martin, Yungui Zhou, Giovanni Manfredi, Giovanni Coppola, Nevan J. Krogan, Daniel H. Geschwind, Li Gan
doi: https://doi.org/10.1101/2021.06.17.448349
Tara E. Tracy
1Gladstone Institutes, San Francisco, CA USA
2Buck Institute for Research on Aging, Novato, CA USA
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Jesus Madero-Pérez
3Helen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
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  • ORCID record for Jesus Madero-Pérez
Danielle Swaney
1Gladstone Institutes, San Francisco, CA USA
4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA USA
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Timothy S. Chang
5Department of Neurology, University of California, Los Angeles, CA USA
aMovement Disorders Program, University of California, Los Angeles, CA USA
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Michelle Moritz
4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA USA
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  • ORCID record for Michelle Moritz
Csaba Konrad
3Helen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
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Michael E. Ward
1Gladstone Institutes, San Francisco, CA USA
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Erica Stevenson
1Gladstone Institutes, San Francisco, CA USA
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Ruth Hüttenhain
1Gladstone Institutes, San Francisco, CA USA
4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA USA
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Grant Kauwe
2Buck Institute for Research on Aging, Novato, CA USA
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Maria Mercedes
3Helen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
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Lauren Sweetland-Martin
3Helen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
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Xu Chen
1Gladstone Institutes, San Francisco, CA USA
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Sue-Ann Mok
6Department of Biochemistry, University of Alberta, Edmonton, AB Canada
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Maria Telpoukhovskaia
1Gladstone Institutes, San Francisco, CA USA
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Sang-Won Min
1Gladstone Institutes, San Francisco, CA USA
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Chao Wang
1Gladstone Institutes, San Francisco, CA USA
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Peter Dongmin Sohn
1Gladstone Institutes, San Francisco, CA USA
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Jordie Martin
1Gladstone Institutes, San Francisco, CA USA
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Yungui Zhou
1Gladstone Institutes, San Francisco, CA USA
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Giovanni Manfredi
3Helen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
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Giovanni Coppola
5Department of Neurology, University of California, Los Angeles, CA USA
bProgram in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA USA
7Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA USA
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Nevan J. Krogan
1Gladstone Institutes, San Francisco, CA USA
4Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA USA
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Daniel H. Geschwind
5Department of Neurology, University of California, Los Angeles, CA USA
aMovement Disorders Program, University of California, Los Angeles, CA USA
bProgram in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, CA USA
8Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA USA
9Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA USA
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Li Gan
1Gladstone Institutes, San Francisco, CA USA
3Helen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
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  • For correspondence: lig2033@med.cornell.edu
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SUMMARY

Tau (MAPT) drives neuronal dysfunction in Alzheimer’s disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau’s interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Tau’s role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

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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Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease
Tara E. Tracy, Jesus Madero-Pérez, Danielle Swaney, Timothy S. Chang, Michelle Moritz, Csaba Konrad, Michael E. Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue-Ann Mok, Maria Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn, Jordie Martin, Yungui Zhou, Giovanni Manfredi, Giovanni Coppola, Nevan J. Krogan, Daniel H. Geschwind, Li Gan
bioRxiv 2021.06.17.448349; doi: https://doi.org/10.1101/2021.06.17.448349
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Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease
Tara E. Tracy, Jesus Madero-Pérez, Danielle Swaney, Timothy S. Chang, Michelle Moritz, Csaba Konrad, Michael E. Ward, Erica Stevenson, Ruth Hüttenhain, Grant Kauwe, Maria Mercedes, Lauren Sweetland-Martin, Xu Chen, Sue-Ann Mok, Maria Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn, Jordie Martin, Yungui Zhou, Giovanni Manfredi, Giovanni Coppola, Nevan J. Krogan, Daniel H. Geschwind, Li Gan
bioRxiv 2021.06.17.448349; doi: https://doi.org/10.1101/2021.06.17.448349

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