Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent speciesNachman, E., Wentink, A. S., Madiona, K., Bousset, L., Katsinelos, T., Allinson, K., Kampinga, H., McEwan, W. A., Jahn, T. R., Melki, R., Mogk, A., Bukau, B. & Nussbaum-Krammer, C., 10-Jul-2020, In : Journal of Biological Chemistry. 295, 28, p. 9676-9690 15 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||15|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - 10-Jul-2020|
- 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