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DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative‐associated proteins
Author(s) -
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,
Dickey Chad A
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593489
Subject(s) - library science , gerontology , medicine , computer science
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, Dna JC 5. In fact, Dna JC 5 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 Dna JC 5 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.