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

The accumulation and prion-like propagation of alpha-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 alpha-synuclein fibrilsin vitro, but its physiological effects on alpha-synuclein toxicity are unknown. Here, we depletedCaenorhabditis elegansHSP-110 and monitored the consequences on alpha-synuclein-related pathological phenotypes such as misfolding, intercellular spreading, and toxicity inC. elegans in vivomodels. 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 alpha-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.