Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Ring, J; Tadic, J; Ristic, S; Poglitsch, M; Bergmann, M; Radic, N; Mossmann, D; Liang, YT; Maglione, M; Jerkovic, A; Hajiraissi, R; Hanke, M; Kuttner, V; Wolinski, H; Zimmermann, A; Trifunovic, LD; Mikolasch, L; Moretti, DN; Broeskamp, F; Westermayer, J; Abraham, C; Schauer, S; Dammbrueck, C; Hofer, SJ; Abdellatif, M; Grundmeier, G; Kroemer, G; Braun, RJ; Hansen, N; Sommer, C; Ninkovic, M; Seba, S; Rockenfeller, P; Vogtle, FN; Dengjel, J; Meisinger, C; Keller, A; Sigrist, SJ; Eisenberg, T; Madeo, F.
The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity
EMBO MOL MED. 2022; e13952
Doi: 10.15252/emmm.202113952
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PubMed
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- Führende Autor*innen der Med Uni Graz
- Eisenberg Tobias
- Tadic Jelena
- Co-Autor*innen der Med Uni Graz
- Abdellatif Mahmoud
- Radic Nemanja
- Rockenfeller Patrick
- Zimmermann Andreas
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- 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.
- Find related publications in this database (Keywords)
- Alzheimer's disease
- amyloid beta 42
- heat shock proteins
- HSP40
- oligomers