Hsp40s play complementary roles in the prevention of tau amyloid formation
- Weizmann Institute of Science, Israel
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
Sharon Grayer Wolf
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.
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.
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Hsp40s play complementary roles in the prevention of tau amyloid formation
eLife 10:e69601.
https://doi.org/10.7554/eLife.69601
