The HSP110/HSP70 disaggregation system generates spreading-competent toxic ?-synuclein species

The accumulation and prion-like propagation of ?-synuclein and other amyloidogenic proteins is 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 ?-synuclein fibrils in vitro, but its physiological effects on ?-synuclein toxicity are unknown. Here, we depleted C. elegans HSP-110, and monitored the consequences on ?-synuclein-related pathological phenotypes such as misfolding, intercellular spreading and toxicity in Caenorhabditis 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 ?-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.