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

Kinneret Rozales, Amal Younis, Naseeb Saida, Anatoly Meller, Hodaya Goldman, Lior Kellerman, Ronit Heinrich, Shai Berlin and Reut Shalgi ()
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Kinneret Rozales: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Amal Younis: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Naseeb Saida: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Anatoly Meller: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Hodaya Goldman: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Lior Kellerman: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Ronit Heinrich: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Shai Berlin: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology
Reut Shalgi: Rappaport Faculty of Medicine, Technion–Israel Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-27982-w

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