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

Publication 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

  • 1,899
    Page views
  • 359
    Downloads
  • 14
    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

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Dario Segura-Peña, Oda Hovet ... Nikolina Sekulic
    Research Article Updated

    Aurora B, together with IN-box, the C-terminal part of INCENP, forms an enzymatic complex that ensures faithful cell division. The [Aurora B/IN-box] complex is activated by autophosphorylation in the Aurora B activation loop and in IN-box, but it is not clear how these phosphorylations activate the enzyme. We used a combination of experimental and computational studies to investigate the effects of phosphorylation on the molecular dynamics and structure of [Aurora B/IN-box]. In addition, we generated partially phosphorylated intermediates to analyze the contribution of each phosphorylation independently. We found that the dynamics of Aurora and IN-box are interconnected, and IN-box plays both positive and negative regulatory roles depending on the phosphorylation status of the enzyme complex. Phosphorylation in the activation loop of Aurora B occurs intramolecularly and prepares the enzyme complex for activation, but two phosphorylated sites are synergistically responsible for full enzyme activity.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Maura Greiser, Mariusz Karbowski ... Liron Boyman
    Research Article

    Mitochondrial ATP production in cardiac ventricular myocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca2+ ([Ca2+]m) and blood flow that is tuned by local ventricular myocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed. We report here on the identity, location, and signaling cascade of a third regulatory system -- CO2/bicarbonate. CO2 is generated in the mitochondrial matrix as a metabolic waste product of the oxidation of nutrients that powers ATP production. It is a lipid soluble gas that rapidly permeates the inner mitochondrial membrane (IMM) and produces bicarbonate (HCO3-) in a reaction accelerated by carbonic anhydrase (CA). The bicarbonate level is tracked physiologically by a bicarbonate-activated adenylyl cyclase, soluble adenylyl cyclase (sAC). Using structural Airyscan super-resolution imaging and functional measurements we find that sAC is primarily inside the mitochondria of ventricular myocytes where it generates cAMP when activated by HCO3-. Our data strongly suggest that ATP production in these mitochondria is regulated by this cAMP signaling cascade operating within the inter-membrane space (IMS) by activating local EPAC1 (Exchange Protein directly Activated by cAMP) which turns on Rap1 (Ras-related protein 1). Thus, mitochondrial ATP production is shown to be increased by bicarbonate-triggered sAC signaling through Rap1. Additional evidence is presented indicating that the cAMP signaling itself does not occur directly in the matrix. We also show that this third signaling process involving bicarbonate and sAC activates the cardiac mitochondrial ATP production machinery by working independently of, yet in conjunction with, [Ca2+]m-dependent ATP production to meet the energy needs of cellular activity in both health and disease. We propose that the bicarbonate and calcium signaling arms function in a resonant or complementary manner to match mitochondrial ATP production to the full range of energy consumption in cardiac ventricular myocytes in health and disease.