Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
Field of Excellence BioHealth, University of Graz, Graz, Austria.
EMBO Mol Med. 2022 May 9;14(5):e13952. doi: 10.15252/emmm.202113952. Epub 2022 Apr 4.
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.
淀粉样蛋白β 42（Abeta42）是阿尔茨海默病（AD）期间神经退行性变的主要触发因素。然而，其有毒细胞效应的病因仍然难以捉摸。在使用酵母模型研究细胞内 Abeta42 毒性的方面的组合遗传和蛋白质组学方法中，我们在这里确定 HSP40 家族成员 Ydj1（人类 DnaJA1 的酵母同源物）是 Abeta42 介导的细胞死亡的关键因素。我们证明 Ydj1/DnaJA1 与 Abeta42（在酵母和小鼠中）物理相互作用，稳定 Abeta42 寡聚物，并介导其易位到线粒体。因此，YDJ1 的缺失强烈减少了 Abeta42 与线粒体的共纯化，并防止了 Abeta42 诱导的线粒体依赖性细胞死亡。一致地，纯化的 DnaJ 伴侣在体外延迟 Abeta42 的纤维化，并且异源表达人 DnaJA1 在体内诱导 Abeta42 寡聚物的形成及其有害易位到线粒体。最后，下调 Ydj1 果蝇同源物 Droj2，可提高黑腹果蝇 AD 模型的应激抗性、线粒体形态和记忆性能。这些数据揭示了特定 HSP40 在促进 Abeta42 毒性特征方面的意外和有害作用。
