The Hsp40 cochaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Protein-encoding nucleotide repeat expansion diseases like polyglutamine (polyQ) and polyglycine (polyG) are linked to misfolded, aggregating proteins.
• Molecular chaperones are being investigated for their potential to suppress disease phenotypes in these conditions.

Purpose of the Study:

• To establish scalable, cell-based models for systematically evaluating genetic modifiers of protein aggregation in both polyQ and polyG diseases.
• To identify novel molecular chaperones and co-chaperones that regulate the aggregation of disease-associated proteins.

Main Methods:

• Development of Förster Resonance Energy Transfer (FRET)-based reporter systems to model polyQ and polyG aggregation in human cells.
• High-throughput CRISPR interference (CRISPRi) screens targeting all known molecular chaperones.
• Analysis of chaperone interactions and effects on protein aggregation.

Main Results:

• CRISPRi screens identified Hsp70 chaperones and Hsp40 co-chaperones as modifiers of polyQ aggregation.
• DNAJC7, an Hsp40 co-chaperone, was identified as a novel and potent suppressor of polyQ aggregation.
• While DNAJC7 did not significantly affect polyG aggregation upon knockdown, its overexpression reduced both polyQ and polyG aggregation and co-localized with aggregates.

Conclusions:

• Established novel inducible, scalable cellular models for studying polyQ and polyG aggregation.
• Expanded the known role of DNAJC7 in regulating the folding and aggregation of disease-associated proteins.
• Highlighted differential chaperone involvement in polyQ versus polyG aggregation pathways.