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

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2022-05-09 eCollection Date: 2022-05-01 DOI:10.15698/cst2022.05.267
Jelena Tadic, Julia Ring, Andrea Jerkovic, Selena Ristic, Marta Maglione, Jörn Dengjel, Stephan J Sigrist, Tobias Eisenberg
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引用次数: 3

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) 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.

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Hsp40蛋白Ydj1/DnaJA1在阿尔茨海默病模型中的病理作用
阿尔茨海默病(AD)是最常见的痴呆症,全世界有数百万人受到影响。AD的病理生理表现包括淀粉样蛋白β (Abeta)肽的细胞外积累,这是淀粉样蛋白前体蛋白APP的蛋白水解裂解产物。越来越多的证据表明,Abeta肽也在细胞内积累,引发线粒体功能障碍等神经毒性事件。然而,驱动细胞内β形成和毒性的分子因素尚不清楚。在我们最近的研究[EMBO Mol Med 2022 - e13952]中,我们使用不同的真核模型系统来识别这些因素。基于酵母的遗传筛选和随后的分子分析,我们发现酵母的伴侣蛋白Ydj1和它的人类同源物DnaJA1都能与Abeta发生物理相互作用,促进Abeta肽聚集成小聚体,并促进它们转运到线粒体。在酵母和果蝇AD模型中,该伴侣蛋白的缺失或下调分别保护了β介导的毒性。最重要的是,在阿尔茨海默病患者的死后人类样本中发现了这种伴侣蛋白的失调。在这里,我们的目标是概述我们的主要发现,强调热休克蛋白(Hsp)家族成员的病理功能,通常认为热休克蛋白在神经变性过程中具有保护作用而不是毒性。因此,我们的研究结果挑战了发展基于伴侣激活的广义疗法的概念,并呼吁仔细考虑特定热休克蛋白的不适应功能。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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