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.

中文翻译：

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HSP40 伴侣 Ydj1 驱动淀粉样蛋白 42 毒性。

淀粉样蛋白 42 (Abeta42) 是阿尔茨海默病 (AD) 期间神经变性的主要诱因。然而，其有害细胞效应的病因学仍然难以捉摸。在使用酵母模型研究细胞内 Abeta42 毒性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，即人类 DnaJA1 的酵母直系同源物，作为 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）进行物理交互，稳定 Abeta42 寡聚体，并介导它们向线粒体的易位。因此，删除 YDJ1 会大大减少 Abeta42 与线粒体的共纯化，并防止 Abeta42 诱导的线粒体依赖性细胞死亡。一贯地，纯化的 DnaJ 伴侣在体外延迟 Abeta42 纤维化，人 DnaJA1 的异源表达诱导 Abeta42 寡聚体的形成及其在体内向线粒体的有害易位。最后，Ydj1 果蝇同系物 Droj2 的下调可改善果蝇 AD 模型的抗压性、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。