Related Experiment Video
Updated: May 22, 2026
06:55
Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
Published on: June 7, 2020
Tau triage decisions mediated by the chaperone network
Casey Cook1, Leonard Petrucelli
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Journal of Alzheimer'S Disease : JAD
|May 19, 2012
Summary
Targeting heat shock protein 90 (Hsp90) with inhibitors can reduce toxic tau protein accumulation in the brain, offering a potential treatment for tauopathies and related neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Pathological tau accumulation is implicated in aging-related neurodegenerative diseases.
- Mechanisms driving tau accumulation remain poorly understood.
Purpose of the Study:
- To review research on Hsp90 inhibition as a therapeutic strategy for tauopathies.
- To elucidate the role of CHIP in Hsp90-mediated tau degradation.
Main Methods:
- Development of a high-throughput screening assay to identify Hsp90 inhibitors.
- Assessment of selective elimination of aberrant tau species in vivo.
- Investigation of CHIP's function within the Hsp90 chaperone complex.
Main Results:
- Hsp90 inhibition selectively eliminates aberrant tau species in the brain.
- CHIP is identified as crucial for Hsp90-mediated tau degradation.
- CHIP regulates Hsp90 activity by modulating HDAC6 levels, affecting tau triage.
Conclusions:
- Hsp90 inhibition shows therapeutic potential for tauopathies.
- Targeting the Hsp90-CHIP-HDAC6 network may promote degradation of pathogenic tau species.
Related Concept Videos
03:00Molecular Chaperones and Protein Folding
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
03:00Molecular Chaperones and Protein Folding
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
01:26Bacterial Protein Maturation
Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
01:37The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
01:37Energy to Drive Translocation
Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
Generally, polypeptides are unfolded by two distinct...
Generally, polypeptides are unfolded by two distinct...