Tau protein aggregates inhibit the protein-folding and vesicular trafficking arms of the cellular proteostasis network

Anan Yu, Susan G. Fox, Annalisa Cavallini, Caroline Kerridge, Michael J. O'Neill, Joanna Wolak, Suchira Bose, Richard I. Morimoto*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations


Tauopathies are a diverse class of neurodegenerative diseases characterized by the formation of insoluble tau aggregates and the loss of cellular function and neuronal death. Tau inclusions have been shown to contain a number of proteins, including molecular chaperones, but the consequences of these entrapments are not well established. Here, using a human cell system for seeding-dependent tau aggregation, we demonstrate that the molecular chaperones heat-shock cognate 71-kDa protein (HSC70)/heat-shock protein 70 (HSP70), HSP90, and J-domain co-chaperones are sequestered by tau aggregates. By employing single-cell analysis of protein-folding and clathrin-mediated endocytosis, we show that both chaperone-dependent cellular activities are significantly impaired by tau aggregation and can be reversed by treatment with small-molecule regulators of heat-shock transcription factor 1 (HSF1) proteostasis that induce the expression of cytosolic chaperones. These results reveal that the sequestration of cytoplasmic molecular chaperones by tau aggregates interferes with two arms of the proteostasis network, likely having profound negative consequences for cellular function.

Original languageEnglish (US)
Pages (from-to)7917-7930
Number of pages14
JournalJournal of Biological Chemistry
Issue number19
StatePublished - May 10 2019


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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