α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation

α-Synuclein aggregation is a hallmark of Parkinson’s disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naïve cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein aggregation. Intracellular aggregates sequester numerous proteins, including subunits of the ESCRT-III system for endolysosome membrane repair, but the toxic effects of these events remain poorly understood. Using cellular models and in vitro reconstitution, we found that α-synuclein fibrils interact with a conserved α-helix in ESCRT-III proteins. This interaction sequesters ESCRT-III subunits and triggers their proteasomal destruction in a process of “collateral degradation.” These twin mechanisms deplete the available ESCRT-III pool, initiating a toxic feedback loop. The ensuing loss of ESCRT function compromises endolysosome membranes, thereby facilitating escape of aggregate seeds into the cytoplasm, facilitating a “second wave” of templated aggregation and ESCRT-III sequestration. We suggest that collateral degradation and triggering of self-perpetuating systems are general mechanisms of sequestration-induced proteotoxicity.