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SHR Neuro Cancer Cardio Lipid Metab 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 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Leading authors Med Uni Graz
Eisenberg Tobias
Tadic Jelena
Co-authors 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
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