The HSP110/HSP70 disaggregation system generates spreading‐competent toxic α‐synuclein species
Jessica Tittelmeier, Carl Alexander Sandhof, H. Ries, Silke Druffel‐Augustin, Axel Mogk, Bernd Bukau, Carmen Nussbaum‐Krammer
Abstract
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. The HSP110/HSP70 chaperone system plays key roles in general protein folding and the disassembly of protein aggregates. A Caenorhabditis elegans model for α‐synuclein aggregation shows that this disaggregase function contributes to the formation of toxic, spreading‐competent amyloid species. Depletion of the HSP70 disaggregase cochaperone HSP110 impairs general cellular protein folding capacity, but at the same time reduces foci formation, cell‐to‐cell transmission, and toxicity of α‐synuclein in a Caenorhabditis elegans model.