The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity

Julia Ring, Jelena Tadic, Selena Ristic, Michael Poglitsch, Martina Bergmann, Nemanja Radic, Dirk Mossmann, Yong Tian Liang, Marta Maglione, Andrea Jerkovic, Roozbeh Hajiraissi, Marcel Hanke, Victoria Küttner, Heimo Wolinski, Andreas Zimmermann, Lana Domuz Trifunović, Leonie Mikolasch, Daiana N. Moretti, Filomena Broeskamp, Julia WestermayerClaudia Abraham, Simon Schauer, Christopher Dammbrueck, Sebastian J. Hofer, Mahmoud Abdellatif, Guido Grundmeier, Guido Kroemer, Ralf J. Braun, Niklas Hansen, Cornelia Sommer, Mirjana Ninkovic, Sandra Seba, Patrick Rockenfeller, Friederike Nora Vögtle, Jörn Dengjel, Chris Meisinger, Adrian Keller, Stephan J. Sigrist, Tobias Eisenberg, Frank Madeo

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    13 Citations (Scopus)

    Abstract

    Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer’s disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor in Abeta42-mediated cell death. We demonstrate that Ydj1/DnaJA1 physically interacts with Abeta42 (in yeast and mouse), stabilizes Abeta42 oligomers, and mediates their translocation to mitochondria. Consequently, deletion of YDJ1 strongly reduces co-purification of Abeta42 with mitochondria and prevents Abeta42-induced mitochondria-dependent cell death. Consistently, purified DnaJ chaperone delays Abeta42 fibrillization in vitro, and heterologous expression of human DnaJA1 induces formation of Abeta42 oligomers and their deleterious translocation to mitochondria in vivo. Finally, downregulation of the Ydj1 fly homologue, Droj2, improves stress resistance, mitochondrial morphology, and memory performance in a Drosophila melanogaster AD model. These data reveal an unexpected and detrimental role for specific HSP40s in promoting hallmarks of Abeta42 toxicity.

    Original languageEnglish
    Article numbere13952
    JournalEMBO Molecular Medicine
    Volume14
    Issue number5
    DOIs
    Publication statusPublished - 9 May 2022

    Keywords

    • Alzheimer’s disease
    • HSP40
    • amyloid beta 42
    • heat shock proteins
    • oligomers

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