Abstract

The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles associated with neurodegenerative conditions, such as Alzheimer's disease. In the cell, however, tau aggregation can be prevented by a class of proteins known as molecular chaperones. While numerous chaperones are known to interact with tau, though, little is known regarding the mechanisms by which these prevent tau aggregation. Here, we describe the effects of ATP-independent Hsp40 chaperones, DNAJA2 and DNAJB1, on tau amyloid-fiber formation, and compare these to the small heat-shock protein HSPB1. We find that the chaperones play complementary roles, with each preventing tau aggregation differently and interacting with distinct sets of tau species. Whereas HSPB1 only binds tau monomers, DNAJB1 and DNAJA2 recognize aggregation-prone conformers and even mature fibers. In addition, we find that both Hsp40s bind tau seeds and fibers via their C-terminal domain II (CTDII), with DNAJA2 being further capable of recognizing tau monomers by a second, distinct site in CTDI. These results lay out the mechanisms by which the diverse members of the Hsp40 family counteract the formation and propagation of toxic tau aggregates, and highlight the fact that chaperones from different families/classes play distinct, yet complementary roles in preventing pathological protein aggregation.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files are provided for Figures 1, 2, 3, and 4 including the full raw unedited gel in figure 2A.

Article and author information

Author details

  1. Rose Irwin

    Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  2. Ofrah Faust

    Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  3. Ivana Petrovic

    Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  4. Sharon Grayer Wolf

    Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5337-5063
  5. Hagen Hofmann

    Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  6. Rina Rosenzweig

    Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    rina.rosenzweig@weizmann.ac.il
    Competing interests
    Rina Rosenzweig, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4019-5135

Funding

H2020 European Research Council (802001)

  • Rina Rosenzweig

Abisch-Frenkel-Stiftung

  • Rina Rosenzweig

Irving and Cherna Moskowitz Center for Nano and Bio-nano Imaging, Weizmann Institute of Science

  • Sharon Grayer Wolf

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Amy Andreotti, Iowa State University, United States

Version history

  1. Preprint posted: April 11, 2021 (view preprint)
  2. Received: April 20, 2021
  3. Accepted: August 8, 2021
  4. Accepted Manuscript published: August 9, 2021 (version 1)
  5. Version of Record published: September 13, 2021 (version 2)

Copyright

© 2021, Irwin 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.

Metrics

  • 2,272
    Page views
  • 411
    Downloads
  • 24
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rose Irwin
  2. Ofrah Faust
  3. Ivana Petrovic
  4. Sharon Grayer Wolf
  5. Hagen Hofmann
  6. Rina Rosenzweig
(2021)
Hsp40s play complementary roles in the prevention of tau amyloid formation
eLife 10:e69601.
https://doi.org/10.7554/eLife.69601

Share this article

https://doi.org/10.7554/eLife.69601

Further reading

    1. Structural Biology and Molecular Biophysics
    Sebastian Jojoa-Cruz, Adrienne E Dubin ... Andrew B Ward
    Research Advance

    The dimeric two-pore OSCA/TMEM63 family has recently been identified as mechanically activated ion channels. Previously, based on the unique features of the structure of OSCA1.2, we postulated the potential involvement of several structural elements in sensing membrane tension (Jojoa-Cruz et al., 2018). Interestingly, while OSCA1, 2, and 3 clades are activated by membrane stretch in cell-attached patches (i.e. they are stretch-activated channels), they differ in their ability to transduce membrane deformation induced by a blunt probe (poking). Here, in an effort to understand the domains contributing to mechanical signal transduction, we used cryo-electron microscopy to solve the structure of Arabidopsis thaliana (At) OSCA3.1, which, unlike AtOSCA1.2, only produced stretch- but not poke-activated currents in our initial characterization (Murthy et al., 2018). Mutagenesis and electrophysiological assessment of conserved and divergent putative mechanosensitive features of OSCA1.2 reveal a selective disruption of the macroscopic currents elicited by poking without considerable effects on stretch-activated currents (SAC). Our results support the involvement of the amphipathic helix and lipid-interacting residues in the membrane fenestration in the response to poking. Our findings position these two structural elements as potential sources of functional diversity within the family.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Tien M Phan, Young C Kim ... Jeetain Mittal
    Research Article

    The heterochromatin protein 1 (HP1) family is a crucial component of heterochromatin with diverse functions in gene regulation, cell cycle control, and cell differentiation. In humans, there are three paralogs, HP1α, HP1β, and HP1γ, which exhibit remarkable similarities in their domain architecture and sequence properties. Nevertheless, these paralogs display distinct behaviors in liquid-liquid phase separation (LLPS), a process linked to heterochromatin formation. Here, we employ a coarse-grained simulation framework to uncover the sequence features responsible for the observed differences in LLPS. We highlight the significance of the net charge and charge patterning along the sequence in governing paralog LLPS propensities. We also show that both highly conserved folded and less-conserved disordered domains contribute to the observed differences. Furthermore, we explore the potential co-localization of different HP1 paralogs in multicomponent assemblies and the impact of DNA on this process. Importantly, our study reveals that DNA can significantly reshape the stability of a minimal condensate formed by HP1 paralogs due to competitive interactions of HP1α with HP1β and HP1γ versus DNA. In conclusion, our work highlights the physicochemical nature of interactions that govern the distinct phase-separation behaviors of HP1 paralogs and provides a molecular framework for understanding their role in chromatin organization.