biostudies-literatureUnknownRamani BNINDS NIH HHSPolyglutamine (polyQ) diseases, including Huntington's disease and several spinocerebellar ataxias, are caused by abnormally expanded CAG nucleotide repeats, which encode aggregation-prone polyQ tracts. Substantial prior evidence supports a pathogenic role for polyQ protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. In this study, we developed a FRET-based reporter system that models polyQ aggregation in human cells and used it to perform a high-throughput CRISPR interference screen targeting all known molecular chaperones. This screen identified as a strong suppressor of polyQ aggregation the Hsp40 co-chaperone DNAJC7, which has previously been shown to modify aggregation of other disease proteins bioRxiv : the preprint server for biology2025.08.10.669490https://www.ebi.ac.uk/biostudies/studies/S-EPMC12363876biostudies-literatureThe Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation.PMC12363876K08 NS133300R25 NS070680Ramani BEhsani KKampmann MfalseThe Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation.Polyglutamine (polyQ) diseases, including Huntington's disease and several spinocerebellar ataxias, are caused by abnormally expanded CAG nucleotide repeats, which encode aggregation-prone polyQ tracts. Substantial prior evidence supports a pathogenic role for polyQ protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. In this study, we developed a FRET-based reporter system that models polyQ aggregation in human cells and used it to perform a high-throughput CRISPR interference screen targeting all known molecular chaperones. This screen identified as a strong suppressor of polyQ aggregation the Hsp40 co-chaperone DNAJC7, which has previously been shown to modify aggregation of other disease proteins 2025-01-01T00:00:00Z2025 Aug2026-07-11T03:16:39.232Z2026-07-11T03:08:31.708ZS-EPMC123638764083227610.1101/2025.08.10.669490