CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation

Hum Mol Genet. 2004 Apr 1;13(7):703-14. doi: 10.1093/hmg/ddh083. Epub 2004 Feb 12.


Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzoquinones
  • Blotting, Western
  • COS Cells
  • Cell Line
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism
  • Detergents / pharmacology
  • Drosophila Proteins / physiology*
  • Genetic Vectors
  • HSP70 Heat-Shock Proteins / physiology*
  • Heat Shock Transcription Factors
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Lac Operon
  • Lactams, Macrocyclic
  • Mice
  • Models, Genetic
  • Molecular Chaperones / chemistry
  • Mutation
  • Nuclear Proteins / physiology*
  • Protein Binding
  • Quinones / pharmacology
  • Subcellular Fractions / metabolism
  • Transcription Factors
  • Transfection
  • Transgenes
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • tau Proteins / metabolism*


  • Benzoquinones
  • Chi protein, Drosophila
  • DNA-Binding Proteins
  • Detergents
  • Drosophila Proteins
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Lactams, Macrocyclic
  • Molecular Chaperones
  • Nuclear Proteins
  • Quinones
  • Transcription Factors
  • Ubiquitin
  • tau Proteins
  • Ubiquitin-Protein Ligases
  • geldanamycin