Dnaj/HSC70 Chaperone Complexes Control the Extracellular Release of Neurodegenerative-Associated Proteins

Authors

Sarah N. Fontaine, University of South Florida
Dali Zheng, University of South Florida
Jonathan J. Sabbagh, University of South Florida
Mackenzie D. Martin, University of South Florida
Dale Chaput, University of South FloridaFollow
April Darling, University of South Florida
Justin H. Trotter, Stanford University
Andrew R. Stothert, University of South Florida
Bryce A. Nordhues, University of South Florida
April Lussier, University of South Florida
Jeremy Baker, University of South Florida
Lindsey Shelton, University of South Florida
Mahnoor Kahn, University of South Florida
Laura J. Blair, University of South FloridaFollow
Stanley M. Stevens, University of South FloridaFollow
Chad A. Dickey, University of South Florida

Document Type

Article

Publication Date

2016

Keywords

DnaJ, extracellular, Hsc70, neurodegeneration, tau

Digital Object Identifier (DOI)

https://doi.org/10.15252/embj.201593489

Abstract

It is now known that proteins associated with neurodegenerative disease can spread throughout the brain in a prionlike manner. However, the mechanisms regulating the trans-synaptic spread propagation, including the neuronal release of these proteins, remain unknown. The interaction of neurodegenerative disease-associated proteins with the molecular chaperone Hsc70 is well known, and we hypothesized that much like disaggregation, refolding, degradation, and even normal function, Hsc70 may dictate the extracellular fate of these proteins. Here, we show that several proteins, including TDP-43, α-synuclein, and the microtubule-associated protein tau, can be driven out of the cell by an Hsc70 co-chaperone, DnaJC5. In fact, DnaJC5 overexpression induced tau release in cells, neurons, and brain tissue, but only when activity of the chaperone Hsc70 was intact and when tau was able to associate with this chaperone. Moreover, release of tau from neurons was reduced in mice lacking the DnaJC5 gene and when the complement of DnaJs in the cell was altered. These results demonstrate that the dynamics of DnaJ/Hsc70 complexes are critically involved in the release of neurodegenerative disease proteins.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

The EMBO Journal, v. 35, issue 14, p. 1537-1549

Scholar Commons Citation

Fontaine, Sarah N.; Zheng, Dali; Sabbagh, Jonathan J.; Martin, Mackenzie D.; Chaput, Dale; Darling, April; Trotter, Justin H.; Stothert, Andrew R.; Nordhues, Bryce A.; Lussier, April; Baker, Jeremy; Shelton, Lindsey; Kahn, Mahnoor; Blair, Laura J.; Stevens, Stanley M.; and Dickey, Chad A., "Dnaj/HSC70 Chaperone Complexes Control the Extracellular Release of Neurodegenerative-Associated Proteins" (2016). Molecular Medicine Faculty Publications. 73.
https://digitalcommons.usf.edu/mme_facpub/73