Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

J Biol Chem. 2020 Jul 10;295(28):9676-9690. doi: 10.1074/jbc.RA120.013478. Epub 2020 May 28.


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 fibrils in 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.

Keywords: 70-kilodalton heat shock protein (Hsp70); Tau; Tau protein; amyloid; chaperone DNAJ (DNAJ); chaperone DnaJ (DnaJ); molecular chaperone; neurodegenerative disease; prion; protein aggregation; proteostasis; tauopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Amyloid* / chemistry
  • Amyloid* / genetics
  • Amyloid* / metabolism
  • Brain* / metabolism
  • Brain* / pathology
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins* / chemistry
  • HSP70 Heat-Shock Proteins* / genetics
  • HSP70 Heat-Shock Proteins* / metabolism
  • Humans
  • tau Proteins* / chemistry
  • tau Proteins* / genetics
  • tau Proteins* / metabolism


  • Amyloid
  • HSP70 Heat-Shock Proteins
  • MAPT protein, human
  • tau Proteins