The Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Polyglutamine (polyQ) diseases result from expanded CAG repeats, leading to protein misfolding and aggregation.
• Molecular chaperones are implicated in modulating protein aggregation and disease phenotypes.
• Previous studies suggest a role for Hsp40 co-chaperones in proteinopathies.

Purpose of the Study:

• To develop a human cell-based reporter system for modeling polyQ aggregation.
• To screen molecular chaperones for their role in suppressing polyQ aggregation using CRISPR interference.
• To investigate the function of DNAJC7 in polyQ and polyglycine (polyG) aggregation.

Main Methods:

• Development of a Förster Resonance Energy Transfer (FRET)-based reporter system for polyQ aggregation in human cells.
• High-throughput CRISPR interference screening of all known molecular chaperones.
• Validation of DNAJC7's effect on polyQ aggregation and investigation of its interaction with polyQ proteins.
• Assessment of DNAJC7's impact on polyG aggregation using a FRET-based model.

Main Results:

• The Hsp40 co-chaperone DNAJC7 was identified as a potent suppressor of polyQ aggregation.
• A physical interaction between DNAJC7 and polyQ-expanded proteins was confirmed.
• DNAJC7 did not affect polyG aggregation, indicating specificity in its function.

Conclusions:

• DNAJC7 plays a significant role in suppressing the aggregation of polyQ proteins associated with neurodegenerative diseases.
• This study establishes novel cellular models for studying polyQ and polyG aggregation.
• The findings expand the known functions of DNAJC7 in regulating the folding of disease-associated proteins.