Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens

Here, using quantitative screens in human cells, the authors reveal distinct effects of naturally-occurring DNAJ chaperone isoforms on pathological aggregation of the Huntington's disease-associated HTT-polyQ and the ALS-related mutant FUS. 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-FL aggravates, HTT-polyQ aggregation. DNAJB14-FL expression increases the mobility of mutFUS aggregates, and restores the deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types.

Automated summary

This study used quantitative screens in human cells to investigate the effects of naturally-occurring DNAJ chaperone isoforms on the pathological aggregation of Huntington's disease-associated HTT-polyQ and ALS-related mutant FUS. The results showed that the aggregation of HTT-polyQ induces a cellular proteotoxic stress response, while mutant FUS aggregation leads to deteriorated proteostasis. The study also revealed complex interactions between different DNAJ isoforms and different aggregate types.