Abstract
The accumulation of amyloid Tau aggregates is implicated in Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here, we show that an ATP-dependent human chaperone system disassembles Tau fibrilsin vitro. We found that this function is mediated by the core chaperone HSC70, assisted by specific cochaperones, in particular class B J-domain proteins and a heat shock protein 110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activity released monomeric and small oligomeric Tau species, which induced the aggregation of self-propagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-edged sword, as it eliminates Tau amyloids at the cost of generating new seeds.
Original language | English |
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Pages (from-to) | 9676-9690 |
Number of pages | 15 |
Journal | Journal of Biological Chemistry |
Volume | 295 |
Issue number | 28 |
DOIs | |
Publication status | Published - 10-Jul-2020 |
Keywords
- Tau protein
- tauopathy
- proteostasis
- amyloid
- protein aggregation
- neurodegenerative disease
- 70-kilodalton heat shock protein (Hsp70)
- chaperone DNAJ (DNAJ)
- molecular chaperone
- prion
- Tau
- chaperone DnaJ (DnaJ)
- GENE-EXPRESSION CHANGES
- ALZHEIMERS-DISEASE
- PROTEIN
- BINDING
- PHOSPHORYLATION
- AGGREGATION
- ASSOCIATION
- PATHOLOGY
- MEDIATE
- HSP110