Tau Protein Aggregates Inhibit the Protein-Folding and Vesicular Trafficking Arms of the Cellular Proteostasis Network

J Biol Chem. 2019 May 10;294(19):7917-7930. doi: 10.1074/jbc.RA119.007527. Epub 2019 Apr 1.

Abstract

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.

Keywords: Clathrin-mediated endocytosis; HSC70; HSP27; HSP70; Tau protein (Tau); chaperone; chaperone competition; heat-shock protein (HSP); heat-shock protein 90 (Hsp90); protein aggregation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytoplasmic Vesicles / genetics
  • Cytoplasmic Vesicles / metabolism*
  • Cytoplasmic Vesicles / pathology
  • HEK293 Cells
  • HSC70 Heat-Shock Proteins / genetics
  • HSC70 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Heat Shock Transcription Factors / genetics
  • Heat Shock Transcription Factors / metabolism
  • Humans
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism*
  • Protein Aggregation, Pathological / pathology
  • Protein Folding*
  • Protein Transport
  • Proteostasis*
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • HSC70 Heat-Shock Proteins
  • HSF1 protein, human
  • HSP90 Heat-Shock Proteins
  • HSPA8 protein, human
  • Heat Shock Transcription Factors
  • tau Proteins