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DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins.

EMBO J. 2016 Jul 15;35(14):1537-49. Epub 2016 Jun 03
Sarah N Fontaine 1 , Dali Zheng 2 , Jonathan J Sabbagh 3 , Mackenzie D Martin 3 , Dale Chaput 4 , April Darling 2 , Justin H Trotter 5 , Andrew R Stothert 2 , Bryce A Nordhues 2 , April Lussier 2 , Jeremy Baker 2 , Lindsey Shelton 2 , Mahnoor Kahn 2 , Laura J Blair 2 , Stanley M Stevens 4 , Chad A Dickey 1
Sarah N Fontaine 1 , Dali Zheng 2 , Jonathan J Sabbagh 3 , Mackenzie D Martin 3 , Dale Chaput 4 , April Darling 2 , Justin H Trotter 5 , Andrew R Stothert 2 , Bryce A Nordhues 2 , April Lussier 2 , Jeremy Baker 2 , Lindsey Shelton 2 , Mahnoor Kahn 2 , Laura J Blair 2 , Stanley M Stevens 4 , Chad A Dickey 1
+ et al

[No authors listed]

Author information
  • 1 Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA James A. Haley Veteran's Hospital, Tampa, FL, USA sarah.fontaine@uky.edu cdickey@health.usf.edu.
  • 2 Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
  • 3 Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA James A. Haley Veteran's Hospital, Tampa, FL, USA.
  • 4 Department of Cell, Molecular and Life Sciences, University of South Florida, Tampa, FL, USA.
  • 5 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.

摘要

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.

KEYWORDS: DnaJ, Hsc70, extracellular, neurodegeneration, tau

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