Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Huntington's disease (HD) is a neurodegenerative disorder linked to expanded CAG repeats in the huntingtin gene (HTT).
• Mutant huntingtin protein (Htt) aggregation is a hallmark of HD, and molecular chaperones are known to modulate this process.
• Understanding chaperone interactions is crucial for developing HD therapeutics.

Purpose of the Study:

• To identify and characterize molecular chaperone complexes that suppress mutant Htt aggregation.
• To investigate the therapeutic potential of targeting chaperone complexes for Huntington's disease.

Main Methods:

• In vitro and in vivo assays were employed to study chaperone complex formation and function.
• HttExon1Q48 and HttExon1Q97 aggregation assays were performed.
• Experiments utilized HEK293T cells, patient-derived neural cells, and Caenorhabditis elegans.

Main Results:

• A trimeric chaperone complex (Hsc70, Hsp110, J-protein) was identified that completely suppresses HttExon1Q48 fibrilization.
• This complex demonstrated the ability to resolubilize existing Htt fibrils.
• The J-protein was identified as the concentration-limiting factor within the complex.
• Single overexpression of DNAJB1 significantly reduced HttExon1Q97 aggregation in HEK293T cells.

Conclusions:

• A specific chaperone complex effectively inhibits and reverses mutant Htt aggregation, offering a novel therapeutic strategy for Huntington's disease.
• The J-protein (DNAJB1) is a critical component and a potential therapeutic target for reducing Htt aggregation in HD.