Screening for molecular chaperones that protect against tau aggregation uncovers links between the co-chaperone DNAJA2 and tau pathology in disease

Identification: Mok, Sue-Ann


Description

Screening for molecular chaperones that protect against tau aggregation uncovers links between the co-chaperone DNAJA2 and tau pathology in disease
 
Sue-Ann Mok1, Carlo Condello1, Rebecca Freilich2,  Anne Gillies2, Taylor Arhar2, Javier Oroz6, Harindranath Kadavath6, Olivier Julien2, Victoria A. Assimon2, Jennifer N. Rauch2, Bryan M. Dunyak2, Jungsoon Lee3, Francis T.F. Tsai3, Mark R. Wilson4, Markus Zweckstetter5,6,7, Chad A. Dickey8, Jason E. Gestwicki1,2 *
1Department of Neurology, 2Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, 94158, USA; 3Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA; 4llawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia; 5Max-Planck-Institut für Biophysikalische Chemie, 37077 Goettingen, Germany; 6Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), von-Siebold-Str. 3a, 37075 Göttingen, Germany; 7Department of Neurology, University Medical Center Göttingen, University of Göttingen, Waldweg 33, 37073 Göttingen, Germany; 8Department of Molecular Medicine and Byrd Alzheimer's Research Institute, University of South Florida, Tampa, Florida 33613, USA
 
A network of molecular chaperones is known to bind proteins (“clients”) and balance their folding, function and turnover. However, it is often not clear 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. In this study, 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 significance, 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.
 
This work was supported by funding from the Tau consortium, BrightFocus Foundation and the NIH (NS059690).
 

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