Data from: The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation

Protein-encoding nucleotide repeat expansion diseases, including
polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized
by the accumulation of aggregation-prone proteins. In the polyQ diseases,
including Huntington’s disease and several spinocerebellar ataxias,
substantial prior evidence supports a pathogenic role for mutant
polyQ-expanded protein misfolding and aggregation, with molecular
chaperones showing promise in suppressing disease phenotypes in cellular
and animal models. The goal of this study is to establish a scalable
cell-based model to systematically evaluate genetic modifiers of protein
aggregation in both polyQ and polyG diseases. We developed FRET-based
reporter systems that model polyQ and polyG aggregation in human cells and
used them to perform high-throughput CRISPR interference screens targeting
all known molecular chaperones. In the polyQ model, the screen identified
multiple Hsp70 chaperones (HSPA8, HSPA4) and Hsp40 co-chaperones (DNAJB6,
DNAJB1) previously implicated in polyQ aggregation and additionally
revealed the Hsp40 co-chaperone DNAJC7 as a potent and previously
unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based
polyG aggregation model of neuronal intranuclear inclusion disease,
CRISPRi screening showed minimal overlap of chaperone modifiers of the
polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG
aggregation, yet overexpressed DNAJC7 co-localized with both polyQ and
polyG aggregates in cells and reduced their aggregation. In addition to
establishing new inducible, scalable cellular models for polyQ and polyG
aggregation, this work expands the role of DNAJC7 in regulating folding of
disease-associated proteins.