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

The following data sets were generated

Article and author information

Author details

  1. Valerie Ann Perez

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8854-515X
  2. David W Sanders

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1835-6895
  3. Ayde Mendoza-Oliva

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Barbara Elena Stopschinski

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5715-4567
  5. Vishruth Mullapudi

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Charles L White III

    Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3870-2804
  7. Lukasz A Joachimiak

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3061-5850
  8. Marc I Diamond

    Center for Alzheimer's and Neurodegenerative Diseases, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    marc.diamond@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8085-7770

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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  1. Valerie Ann Perez
  2. David W Sanders
  3. Ayde Mendoza-Oliva
  4. Barbara Elena Stopschinski
  5. Vishruth Mullapudi
  6. Charles L White III
  7. Lukasz A Joachimiak
  8. Marc I Diamond
(2023)
DnaJC7 specifically regulates tau seeding
eLife 12:e86936.
https://doi.org/10.7554/eLife.86936

Share this article

https://doi.org/10.7554/eLife.86936

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