DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins.
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.
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.
Sarah N
SN
Fontaine
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Dali
D
Zheng
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.
Jonathan J
JJ
Sabbagh
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.
Mackenzie D
MD
Martin
Department of Cell, Molecular and Life Sciences, University of South Florida, Tampa, FL, USA.
Dale
D
Chaput
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
April
A
Darling
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
Justin H
JH
Trotter
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Andrew R
AR
Stothert
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Bryce A
BA
Nordhues
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
April
A
Lussier
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Jeremy
J
Baker
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Lindsey
L
Shelton
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Mahnoor
M
Kahn
Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.
Laura J
LJ
Blair
Department of Cell, Molecular and Life Sciences, University of South Florida, Tampa, FL, USA.
Stanley M
SM
Stevens
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.
Chad A
0000-0003-3834-3159
CA
Dickey
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; C494371:HSPA8 protein, human; D008565:Membrane Proteins; C000598624:TARDBP protein, human; D051844:alpha-Synuclein; C088460:cysteine string protein; D016875:tau Proteins
DnaJ; Hsc70; extracellular; neurodegeneration; tau