EMBO Molecular Medicine (May 2022)
The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity
- Julia Ring,
- Jelena Tadic,
- Selena Ristic,
- Michael Poglitsch,
- Martina Bergmann,
- Nemanja Radic,
- Dirk Mossmann,
- YongTian 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 Westermayer,
- Claudia 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
Affiliations
- Julia Ring
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Jelena Tadic
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Selena Ristic
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Michael Poglitsch
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Martina Bergmann
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Nemanja Radic
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Dirk Mossmann
- Institute for Biochemistry and Molecular Biology ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany
- YongTian Liang
- NeuroCure Charité Berlin Berlin Germany
- Marta Maglione
- NeuroCure Charité Berlin Berlin Germany
- Andrea Jerkovic
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Roozbeh Hajiraissi
- Technical and Macromolecular Chemistry Paderborn University Paderborn Germany
- Marcel Hanke
- Technical and Macromolecular Chemistry Paderborn University Paderborn Germany
- Victoria Küttner
- Department of Dermatology Medical Center Freiburg Institute for Advanced Studies (FRIAS) University of Freiburg Freiburg Germany
- Heimo Wolinski
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Andreas Zimmermann
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Lana Domuz Trifunović
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Leonie Mikolasch
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Daiana N Moretti
- Institute of Biochemistry and Molecular Biology ZBMZ Faculty of Medicine University of Freiburg Freiburg Germany
- Filomena Broeskamp
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Julia Westermayer
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Claudia Abraham
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Simon Schauer
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Christopher Dammbrueck
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Sebastian J Hofer
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Mahmoud Abdellatif
- Department of Cardiology Medical University of Graz Graz Austria
- Guido Grundmeier
- Technical and Macromolecular Chemistry Paderborn University Paderborn Germany
- Guido Kroemer
- Centre de Recherche des Cordeliers Equipe labellisée par la Ligue contre le cancer Université de Paris Sorbonne Université, Inserm U1138, Institut Universitaire de France Paris France
- Ralf J Braun
- Research Division for Neurodegenerative Diseases Center for Biosciences Department of Medicine Faculty of Medicine and Dentistry Danube Private University Krems Austria
- Niklas Hansen
- Technical and Macromolecular Chemistry Paderborn University Paderborn Germany
- Cornelia Sommer
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Mirjana Ninkovic
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Sandra Seba
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Patrick Rockenfeller
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Friederike‐Nora Vögtle
- Institute for Biochemistry and Molecular Biology ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany
- Jörn Dengjel
- Department of Dermatology Medical Center Freiburg Institute for Advanced Studies (FRIAS) University of Freiburg Freiburg Germany
- Chris Meisinger
- Institute for Biochemistry and Molecular Biology ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg Germany
- Adrian Keller
- Technical and Macromolecular Chemistry Paderborn University Paderborn Germany
- Stephan J Sigrist
- NeuroCure Charité Berlin Berlin Germany
- Tobias Eisenberg
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- Frank Madeo
- Institute of Molecular Biosciences NAWI Graz University of Graz Graz Austria
- DOI
- https://doi.org/10.15252/emmm.202113952
- Journal volume & issue
-
Vol. 14,
no. 5
pp. n/a – n/a
Abstract
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.
Keywords