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Human Molecular Genetics Advance Access originally published online on February 12, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 7 703-714
DOI: 10.1093/hmg/ddh083

CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation

Leonard Petrucelli1, Dennis Dickson1, Kathryn Kehoe1, Julie Taylor1, Heather Snyder2, Andrew Grover1, Michael De Lucia1, Eileen McGowan1, Jada Lewis1, Guy Prihar1, Jungsu Kim1, Wolfgang H. Dillmann3, Susan E. Browne4, Alexis Hall5, Richard Voellmy5, Yoshio Tsuboi6, Ted M. Dawson7,8,9, Benjamin Wolozin2, John Hardy10 and Mike Hutton1,*

1Mayo Clinic, Jacksonville, FL 32224, USA, 2Loyola University School of Medicine, Department of Pharmacology, Maywood, IL 60153, USA, 3University of California, Department of Medicine, La Jolla, CA, USA, 4Weill Medical College of Cornell University, New York, NY 10021, USA, 5University of Miami School of Medicine, Miami, FL 33136, USA, 6Fukuoka University, Department of Internal Medicine, Japan, 7Institute for Cell Engineering, 8Department of Neurology, 9Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 10National Institutes of Health, Department of Neurogenetics, Bethseda, MD 20892, USA

Received November 17, 2003; Accepted January 30, 2004

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.

* To whom correspondence should be addressed at: Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Email: hutton.michael{at}mayo.edu


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