A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease
Authors:Jelena Tadic1,2, Julia Ring1, Andrea Jerkovic1, Selena Ristic1, Marta Maglione3,4, Jörn Dengjel5, Stephan J. Sigrist3,4 and Tobias Eisenberg1,2,6
1 Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
2 Field of Excellence BioHealth, University of Graz, Graz, Austria.
3 NeuroCure Charité Berlin, Berlin, Germany.
4 Institute for Biology, Freie Universität Berlin, Berlin, Germany.
5 Department of Biology, University of Fribourg, Fribourg, Switzerland.
6 BioTechMed-Graz, 8010 Graz, Austria.
Keywords:
Alzheimer’s disease, amyloid beta 42, oligomers, heat shock proteins, HSP40, Ydj1, DnaJA1, yeast cell death, Drosophila, neurodegeneration.
Corresponding Author(s):
Conflict of interest statement:
Authors declare no conflict of interest.
Please cite this article as:
Jelena Tadic, Julia Ring, Andrea Jerkovic, Selena Ristic, Marta Maglione, Jörn Dengjel, Stephan J. Sigrist and Tobias Eisenberg (2022). A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease. Cell Stress 6(5): 61-64. doi: 10.15698/cst2022.05.267
© 2022 Tadic et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
Alzheimer’s disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) peptides, products of the proteolytic cleavage of the amyloid precursor protein APP. Increasing evidence suggests that Abeta peptides also accumulate intracellularly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 – e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facilitate the aggregation of Abeta peptides into small oligomers and promote their translocation to mitochondria. Deletion or downregulation of this chaperone protected from Abeta-mediated toxicity in yeast and Drosophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus challenge the concept of developing generalized chaperone activation-based therapies and call for carefully considering also maladaptive functions of specific heat shock proteins.