The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity
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 toxic...
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Springer Nature
2022-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202113952 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Julia Ring |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4c65d2eea54842d29ae6240b593bf7ff |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-04-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-4c65d2eea54842d29ae6240b593bf7ff2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-04-0114512610.15252/emmm.202113952The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicityJulia Ring0Jelena Tadic1Selena Ristic2Michael Poglitsch3Martina Bergmann4Nemanja Radic5Dirk Mossmann6YongTian Liang7Marta Maglione8Andrea Jerkovic9Roozbeh Hajiraissi10Marcel Hanke11Victoria Küttner12Heimo Wolinski13Andreas Zimmermann14Lana Domuz Trifunović15Leonie Mikolasch16Daiana N Moretti17Filomena Broeskamp18Julia Westermayer19Claudia Abraham20Simon Schauer21Christopher Dammbrueck22Sebastian J Hofer23Mahmoud Abdellatif24Guido Grundmeier25Guido Kroemer26Ralf J Braun27Niklas Hansen28Cornelia Sommer29Mirjana Ninkovic30Sandra Seba31Patrick Rockenfeller32Friederike‐Nora Vögtle33Jörn Dengjel34Chris Meisinger35Adrian Keller36Stephan J Sigrist37Tobias Eisenberg38Frank Madeo39Institute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute for Biochemistry and Molecular Biology, ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies, University of FreiburgNeuroCure Charité BerlinNeuroCure Charité BerlinInstitute of Molecular Biosciences, NAWI Graz, University of GrazTechnical and Macromolecular Chemistry, Paderborn UniversityTechnical and Macromolecular Chemistry, Paderborn UniversityDepartment of Dermatology, Medical Center, Freiburg Institute for Advanced Studies (FRIAS), University of FreiburgInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of FreiburgInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazDepartment of Cardiology, Medical University of GrazTechnical and Macromolecular Chemistry, Paderborn UniversityCentre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de FranceResearch Division for Neurodegenerative Diseases, Center for Biosciences, Department of Medicine, Faculty of Medicine and Dentistry, Danube Private UniversityTechnical and Macromolecular Chemistry, Paderborn UniversityInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute for Biochemistry and Molecular Biology, ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies, University of FreiburgDepartment of Dermatology, Medical Center, Freiburg Institute for Advanced Studies (FRIAS), University of FreiburgInstitute for Biochemistry and Molecular Biology, ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies, University of FreiburgTechnical and Macromolecular Chemistry, Paderborn UniversityNeuroCure Charité BerlinInstitute of Molecular Biosciences, NAWI Graz, University of GrazInstitute of Molecular Biosciences, NAWI Graz, University of GrazAbstract 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.https://doi.org/10.15252/emmm.202113952Alzheimer’s diseaseamyloid beta 42heat shock proteinsHSP40oligomers |
| spellingShingle | 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 The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity EMBO Molecular Medicine Alzheimer’s disease amyloid beta 42 heat shock proteins HSP40 oligomers |
| title | The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity |
| title_full | The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity |
| title_fullStr | The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity |
| title_full_unstemmed | The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity |
| title_short | The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity |
| title_sort | hsp40 chaperone ydj1 drives amyloid beta 42 toxicity |
| topic | Alzheimer’s disease amyloid beta 42 heat shock proteins HSP40 oligomers |
| url | https://doi.org/10.15252/emmm.202113952 |
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