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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202113952 |
| _version_ | 1797283028426293248 |
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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. |
| first_indexed | 2024-03-07T17:25:11Z |
| format | Article |
| id | doaj.art-4c65d2eea54842d29ae6240b593bf7ff |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:25:11Z |
| publishDate | 2022-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-4c65d2eea54842d29ae6240b593bf7ff2024-03-02T19:21:07ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-05-01145n/an/a10.15252/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 Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute for Biochemistry and Molecular Biology ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg GermanyNeuroCure Charité Berlin Berlin GermanyNeuroCure Charité Berlin Berlin GermanyInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaTechnical and Macromolecular Chemistry Paderborn University Paderborn GermanyTechnical and Macromolecular Chemistry Paderborn University Paderborn GermanyDepartment of Dermatology Medical Center Freiburg Institute for Advanced Studies (FRIAS) University of Freiburg Freiburg GermanyInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Biochemistry and Molecular Biology ZBMZ Faculty of Medicine University of Freiburg Freiburg GermanyInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaDepartment of Cardiology Medical University of Graz Graz AustriaTechnical and Macromolecular Chemistry Paderborn University Paderborn GermanyCentre de Recherche des Cordeliers Equipe labellisée par la Ligue contre le cancer Université de Paris Sorbonne Université, Inserm U1138, Institut Universitaire de France Paris FranceResearch Division for Neurodegenerative Diseases Center for Biosciences Department of Medicine Faculty of Medicine and Dentistry Danube Private University Krems AustriaTechnical and Macromolecular Chemistry Paderborn University Paderborn GermanyInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute for Biochemistry and Molecular Biology ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg GermanyDepartment of Dermatology Medical Center Freiburg Institute for Advanced Studies (FRIAS) University of Freiburg Freiburg GermanyInstitute for Biochemistry and Molecular Biology ZBMZ, Medical Faculty and CIBSS ‐ Centre for Integrative Biological Signalling Studies University of Freiburg Freiburg GermanyTechnical and Macromolecular Chemistry Paderborn University Paderborn GermanyNeuroCure Charité Berlin Berlin GermanyInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaInstitute of Molecular Biosciences NAWI Graz University of Graz Graz AustriaAbstract 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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