Self-association of amyloidogenic proteins is the main pathological trigger in a wide variety of neurodegenerative disorders. These aggregates are deposited inside or outside the cell due to hereditary mutations, environmental exposures or even normal aging. Cumulative evidence indicates that the heat shock chaperone Hsp70 possesses robust neuroprotection against various intracellular amyloids in Drosophila and mouse models. However, its protective role against extracellular amyloids was largely unknown as its presence outside the cells is very limited. Our recent manuscript in PNAS revealed that an engineered form of secreted Hsp70 (secHsp70) is highly protective against toxicity induced by extracellular deposition of the amyloid-β42 (Aβ42) peptide. In this Extra View article, we extend our analysis to other members of the heat shock protein family. We created PhiC31-based transgenic lines for human Hsp27, Hsp40, Hsp60 and Hsp70 and compared their activities in parallel against extracellular Aβ42. Strikingly, only secreted Hsp70 exhibits robust protection against Aβ42-triggered toxicity in the extracellular milieu. These observations indicate that the ability of secHsp70 to suppress Aβ42 insults is quite unique and suggest that targeted secretion of Hsp70 may represent a new therapeutic approach against Aβ42 and other extracellular amyloids. The potential applications of this engineered chaperone are discussed.

淀粉样蛋白的自我结合是多种神经退行性疾病的主要病理触发因素。由于遗传突变、环境暴露甚至正常老化，这些聚集体沉积在细胞内部或外部。累积证据表明，热休克伴侣 Hsp70 对果蝇和小鼠模型中的各种细胞内淀粉样蛋白具有强大的神经保护作用。然而，它对细胞外淀粉样蛋白的保护作用在很大程度上是未知的，因为它在细胞外的存在非常有限。我们最近在 PNAS 上的手稿揭示了一种工程形式的分泌 Hsp70 (secHsp70) 对淀粉样蛋白-β42 (Aβ42) 肽的细胞外沉积引起的毒性具有高度保护作用。在这篇额外的观点文章中，我们将分析扩展到热休克蛋白家族的其他成员。我们为人类 Hsp27、Hsp40、Hsp60 和 Hsp70 创建了基于 PhiC31 的转基因系，并同时比较了它们与细胞外 Aβ42 的活性。引人注目的是，只有分泌的 Hsp70 在细胞外环境中表现出对 Aβ42 引发的毒性的强大保护作用。这些观察表明 secHsp70 抑制 Aβ42 损伤的能力非常独特，并表明 Hsp70 的靶向分泌可能代表了一种针对 Aβ42 和其他细胞外淀粉样蛋白的新治疗方法。讨论了这种工程伴侣的潜在应用。只有分泌的 Hsp70 在细胞外环境中表现出对 Aβ42 引发的毒性的强大保护作用。这些观察表明 secHsp70 抑制 Aβ42 损伤的能力非常独特，并表明 Hsp70 的靶向分泌可能代表了一种针对 Aβ42 和其他细胞外淀粉样蛋白的新治疗方法。讨论了这种工程伴侣的潜在应用。只有分泌的 Hsp70 在细胞外环境中表现出对 Aβ42 引发的毒性的强大保护作用。这些观察表明 secHsp70 抑制 Aβ42 损伤的能力非常独特，并表明 Hsp70 的靶向分泌可能代表了一种针对 Aβ42 和其他细胞外淀粉样蛋白的新治疗方法。讨论了这种工程伴侣的潜在应用。