CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation

Leonard Petrucelli, Dennis W Dickson, Kathryn Kehoe, Julie Taylor, Heather Snyder, Andrew Grover, Michael De Lucia, Eileen McGowan, Jada Lewis, Guy Prihar, Jungsu Kim, Wolfgang H. Dillmann, Susan E. Browne, Alexis Hall, Richard Voellmy, Yoshio Tsuboi, Ted M. Dawson, Benjamin Wolozin, John Hardy, Mike Hutton

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Abstract

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 α-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.

Original languageEnglish (US)
Pages (from-to)703-714
Number of pages12
JournalHuman Molecular Genetics
Volume13
Issue number7
DOIs
StatePublished - Apr 1 2004

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ASJC Scopus subject areas

  • Genetics

Cite this

Petrucelli, L., Dickson, D. W., Kehoe, K., Taylor, J., Snyder, H., Grover, A., De Lucia, M., McGowan, E., Lewis, J., Prihar, G., Kim, J., Dillmann, W. H., Browne, S. E., Hall, A., Voellmy, R., Tsuboi, Y., Dawson, T. M., Wolozin, B., Hardy, J., & Hutton, M. (2004). CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Human Molecular Genetics, 13(7), 703-714. https://doi.org/10.1093/hmg/ddh083