A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease

Cell Stress

Jörn Dengjel¹  Selena Ristic²  Jelena Tadic²  Julia Ring²  Andrea Jerkovic²  Tobias Eisenberg²  Stephan J. Sigrist³  Marta Maglione³ 

[1] Department of Biology, University of Fribourg, Fribourg, Switzerland.;Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.;NeuroCure Charité Berlin, Berlin, Germany.;

关键词: alzheimer’s disease;    amyloid beta 42;    oligomers;    heat shock proteins;    hsp40;    ydj1;    dnaja1;    yeast cell death;    drosophila;    neurodegeneration;   

DOI  :  10.15698/cst2022.05.267

来源: DOAJ

【 摘 要 】

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) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, 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, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila 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 chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins.

【 授权许可】

Unknown