biostudies-literatureRozales KEuropean Research Council516https://www.ebi.ac.uk/biostudies/studies/S-EPMC8792056biostudies-literatureUnknown13(1)Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington's disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-FNature communicationsDifferential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.PMC8792056677776851919Goldman HShalgi RSaida NYounis AMeller ABerlin SRozales KKellerman LHeinrich RfalseDifferential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington's disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-F2022-01-01T00:00:00Z2022 Jan2026-05-31T01:15:55.778Z2024-11-09T08:01:10.949ZS-EPMC87920563508230110.1038/s41467-022-27982-w