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CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation
Leonard Petrucelli1, Dennis Dickson, Kathryn Kehoe
1Mayo Clinic, Jacksonville, FL 32224, USA.
Human Molecular Genetics
|February 14, 2004
Summary
The Hsp70/CHIP chaperone system regulates tau protein turnover, reducing abnormal tau species implicated in neurodegenerative diseases like Alzheimer's. This system represents a potential therapeutic target for tauopathies.
Area of Science:
- Neurobiology
- Molecular Biology
- Protein Degradation
Background:
- Neurodegenerative diseases such as Alzheimer's and Parkinson's are linked to protein aggregate accumulation.
- Molecular chaperones, ubiquitin ligases, and proteasome dysfunction are implicated in these diseases.
- Tau and alpha-synuclein are key proteins forming aggregates in Alzheimer's and Parkinson's, respectively.
Purpose of the Study:
- To investigate the role of CHIP (carboxyl terminus of Hsp70-interacting protein) in tau ubiquitination and aggregation.
- To explore the therapeutic potential of the Hsp70/CHIP chaperone system in regulating tau pathology.
Main Methods:
- Examined CHIP's interaction with Hsp70/90 and its effect on tau ubiquitination.
- Assessed tau aggregation and levels in response to CHIP and Hsp70 modulation.
- Utilized human postmortem brain tissue and transgenic mouse models overexpressing inducible Hsp70.
Main Results:
- CHIP induces tau ubiquitination and enhances tau aggregation.
- CHIP is found in tau lesions in human brain tissue.
- Hsp70 induction reduces tau steady-state levels and insoluble tau species.
- Hsp70 overexpression in aged mice significantly decreased tau levels.
Conclusions:
- The Hsp70/CHIP chaperone system is crucial for regulating tau turnover and eliminating abnormal tau species.
- This system plays a significant role in the pathogenesis of tauopathies.
- The Hsp70/CHIP system presents a promising therapeutic target for tauopathies.