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The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity
Julia Ring1, Jelena Tadic1,2, Selena Ristic1
1Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
EMBO Molecular Medicine
|April 4, 2022
Summary
Heat shock protein 40 (HSP40) family member Ydj1/DnaJA1 promotes amyloid beta 42 (Abeta42) toxicity in Alzheimer's disease models. This protein mediates Abeta42 translocation to mitochondria, causing cell death.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Amyloid beta 42 (Abeta42) is implicated in Alzheimer's disease (AD) neurodegeneration.
- The precise mechanisms of Abeta42 cellular toxicity are not fully understood.
Purpose of the Study:
- To investigate the molecular factors contributing to intracellular Abeta42 toxicity.
- To identify novel therapeutic targets for Alzheimer's disease.
Main Methods:
- Utilized a yeast model for genetic and proteomic analysis of Abeta42 toxicity.
- Investigated protein-protein interactions between Abeta42 and HSP40 family members.
- Employed Drosophila melanogaster models to assess in vivo effects.
Main Results:
- Identified Ydj1 (yeast orthologue of human DnaJA1) as a key mediator of Abeta42 toxicity.
- Demonstrated that Ydj1/DnaJA1 stabilizes Abeta42 oligomers and facilitates their mitochondrial translocation.
- Deletion of YDJ1 protected against Abeta42-induced cell death and reduced mitochondrial Abeta42 co-purification.
- Downregulation of the fly homologue Droj2 improved AD model phenotypes.
Conclusions:
- Specific HSP40 proteins, like Ydj1/DnaJA1, play a detrimental role in promoting Abeta42-mediated neurodegeneration.
- Targeting HSP40 chaperones may offer a novel therapeutic strategy for Alzheimer's disease.
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