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

Author

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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)

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.

Suggested Citation

  • Kinneret Rozales & Amal Younis & Naseeb Saida & Anatoly Meller & Hodaya Goldman & Lior Kellerman & Ronit Heinrich & Shai Berlin & Reut Shalgi, 2022. "Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-27982-w
    DOI: 10.1038/s41467-022-27982-w
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    Cited by:

    1. Jaime Carrasco & Rosa Antón & Alejandro Valbuena & David Pantoja-Uceda & Mayur Mukhi & Rubén Hervás & Douglas V. Laurents & María Gasset & Javier Oroz, 2023. "Metamorphism in TDP-43 prion-like domain determines chaperone recognition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Rebecca San Gil & Dana Pascovici & Juliana Venturato & Heledd Brown-Wright & Prachi Mehta & Lidia Madrid San Martin & Jemma Wu & Wei Luan & Yi Kit Chui & Adekunle T. Bademosi & Shilpa Swaminathan & Se, 2024. "A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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