The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity.
Alzheimer’s disease
HSP40
amyloid beta 42
heat shock proteins
oligomers
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
09 05 2022
09 05 2022
Historique:
revised:
12
02
2022
received:
13
01
2021
accepted:
15
02
2022
pubmed:
5
4
2022
medline:
11
5
2022
entrez:
4
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35373908
doi: 10.15252/emmm.202113952
pmc: PMC9081910
doi:
Substances chimiques
Amyloid beta-Peptides
0
Dnaja1 protein, mouse
0
HSP40 Heat-Shock Proteins
0
Molecular Chaperones
0
Peptide Fragments
0
Saccharomyces cerevisiae Proteins
0
amyloid beta-protein (1-42)
0
YDJ1 protein, S cerevisiae
139874-78-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13952Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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