DnaJC7 specifically regulates tau seeding
- The University of Texas Southwestern Medical Center, United States
Abstract
Neurodegenerative tauopathies are caused by accumulation of toxic tau protein assemblies. This appears to involve template-based seeding events, whereby tau monomer changes conformation and is recruited to a growing aggregate. Several large families of chaperone proteins, including Hsp70s and J domain proteins (JDPs) cooperate to regulate the folding of intracellular proteins such as tau, but the factors that coordinate this activity are not well known. The JDP DnaJC7 binds tau and reduces its intracellular aggregation. However, it is unknown whether this is specific to DnaJC7 or if other JDPs might be similarly involved. We used proteomics within a cell model to determine that DnaJC7 co-purified with insoluble tau and colocalized with intracellular aggregates. We individually knocked out every possible JDP and tested the effect on intracellular aggregation and seeding. DnaJC7 knockout decreased aggregate clearance and increased intracellular tau seeding. This depended on the ability of the J domain (JD) of DnaJC7 to stimulate Hsp70 ATPase activity, as JD mutations that block this interaction abrogated the protective activity. Disease-associated mutations in the JD and substrate binding site of DnaJC7 also abolished its protective activity. DnaJC7 thus specifically regulates tau aggregation in cooperation with Hsp70.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file. Source Data files for included Western Blot images are provided as Figure 1 - Supplement 1 - Source Data 1, Figure 2 - Supplement 1 - Source Data 1, Figure 3 -Supplement 1 - Source Data 1, and Figure 5 - Supplement 1 - Source Data 1. Source data files have been provided for Figures 1 (Source Data 1 and 2) and 2 (Source Data 3) on Dryad at: https://doi.org/10.5061/dryad.fj6q57402FCS files are deposited on Cytobank at: https://community.cytobank.org/cytobank/projects/1505
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DnaJC7 specifically regulates tau seedingDryad Digital Repository, doi:10.5061/dryad.fj6q57402.
Article and author information
Author details
Barbara Elena Stopschinski
Charles L White III
Lukasz A Joachimiak
Funding
National Institute on Aging (RF1AG078888)
- Valerie Ann Perez
- Vishruth Mullapudi
- Lukasz A Joachimiak
National Institute on Aging (3R01AG048678)
- Valerie Ann Perez
- David W Sanders
- Ayde Mendoza-Oliva
- Barbara Elena Stopschinski
- Marc I Diamond
National Institute on Aging (1RF1AG059689)
- Valerie Ann Perez
- David W Sanders
- Ayde Mendoza-Oliva
- Barbara Elena Stopschinski
- Charles L White III
- Marc I Diamond
National Institute on Aging (1RF1AG065407)
- Valerie Ann Perez
- David W Sanders
- Ayde Mendoza-Oliva
- Barbara Elena Stopschinski
- Vishruth Mullapudi
- Lukasz A Joachimiak
- Marc I Diamond
McCune Foundation
- Charles L White III
Winspear Family Center for Research on the Neuropathology of Alzheimer's Disease
- Charles L White III
Chan Zuckerberg Initiative (2018-191983)
- Charles L White III
- Lukasz A Joachimiak
- Marc I Diamond
Chan Zuckerberg Initiative (2021-237348)
- Charles L White III
- Lukasz A Joachimiak
- Marc I Diamond
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Perez et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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DnaJC7 specifically regulates tau seeding
eLife 12:e86936.
https://doi.org/10.7554/eLife.86936
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