The accumulation and prion‐like propagation of α‐synuclein and other amyloidogenic proteins are associated with devastating neurodegenerative diseases. Metazoan heat shock protein HSP70 and its co‐chaperones DNAJB1 and HSP110 constitute a disaggregation machinery that is able to disassemble α‐synuclein fibrils in vitro , but its physiological effects on α‐synuclein toxicity are unknown. Here, we depleted Caenorhabditis elegans HSP‐110 and monitored the consequences on α‐synuclein‐related pathological phenotypes such as misfolding, intercellular spreading, and toxicity in C. elegans in vivo models. Depletion of HSP‐110 impaired HSP70 disaggregation activity, prevented resolubilization of amorphous aggregates, and compromised the overall cellular folding capacity. At the same time, HSP‐110 depletion reduced α‐synuclein foci formation, cell‐to‐cell transmission, and toxicity. These data demonstrate that the HSP70 disaggregation activity constitutes a double‐edged sword, as it is essential for maintaining cellular proteostasis but also involved in the generation of toxic amyloid‐type protein species.

中文翻译：

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HSP110 / HSP70分解系统产生具有扩散能力的有毒α-突触核蛋白。

α-突触核蛋白和其他淀粉样蛋白的积累和病毒样繁殖与破坏性神经退行性疾病有关。后生动物热激蛋白HSP70及其伴侣DNAJB1和HSP110构成了能够在体外分解α-突触核蛋白原纤维的分解机制，但其对α-突触核蛋白毒性的生理作用尚不清楚。在这里，我们耗尽了秀丽隐杆线虫HSP-110，并监测了与秀丽隐杆线虫体内的错误折叠，细胞间扩散和毒性有关的α-突触核蛋白相关病理表型的后果楷模。HSP-110的消耗会破坏HSP70的分解活性，阻止无定形聚集体的再溶解，并损害总体细胞折叠能力。同时，HSP-110的消耗减少了α-突触核蛋白灶的形成，细胞间传递和毒性。这些数据表明，HSP70的分解活性构成了一把双刃剑，因为它对维持细胞蛋白稳态至关重要，但也参与了有毒淀粉样蛋白种类的产生。