Mapping interactions with the chaperone network reveals factors that protect against tau aggregation

Authors

Sue-Ann Mok, University of California at San Francisco
Carlo Condello, University of California at San Francisco
Rebecca Freilich, University of California at San Francisco
Anne Gillies, University of California at San Francisco
Taylor Arhar, University of California at San Francisco
Javier Oroz, German Center for Neurodegenerative Diseases
Harindranath Kadavath, German Center for Neurodegenerative Diseases
Olivier Julien, University of California at San Francisco
Victoria A. Assimon, University of California at San Francisco
Jennifer N. Rauch, University of California at San Francisco
Bryan M. Dunyak, University of California at San Francisco
Jungsoon Lee, Baylor College Of Medicine
Francis T. F Tsai, Baylor College Of Medicine
Mark R. Wilson, University of WollongongFollow
Markus Zweckstetter, German Center for Neurodegenerative Diseases, Max-Planck-Institut fur Biophysikalische Chemie, University of Gottingen
Chad A. Dickey, University of South Florida
Jason E. Gestwicki, University of California at San Francisco

RIS ID

127521

Publication Details

Mok, S., Condello, C., Freilich, R., Gillies, A., Arhar, T., Oroz, J., Kadavath, H., Julien, O., Assimon, V. A., Rauch, J. N., Dunyak, B. M., Lee, J., Tsai, F. T. F., Wilson, M. R., Zweckstetter, M., Dickey, C. A. & Gestwicki, J. E. (2018). Mapping interactions with the chaperone network reveals factors that protect against tau aggregation. Nature Structural and Molecular Biology, 25 (5), 384-393.

Abstract

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ∼30 purified chaperones and ∼20 disease-associated tau variants (∼600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease.