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

Sitron, Cole S. ; Trinkaus, Victoria A. ; Galesic, Ana ; Garhammer, Maximilian ; Yuste-Checa, Patricia ; Dransfeld, Ulrich ; Feigenbutz, Dennis ; Zhang, Jiuchun; Ivashko, Larysa; Dudanova, Irina ; Harper, J. Wade und Hartl, F. Ulrich (2025): α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation. In: Molecular Cell, Bd. 85, Nr. 18: S. 3505-3523

Abstract

α-Synuclein aggregation is a hallmark of Parkinson’s disease and related synucleinopathies. Extracellular α-synuclein fibrils enter naive cells via endocytosis, followed by transit into the cytoplasm to seed endogenous α-synuclein aggregation. Intracellular aggregates sequester numerous proteins, including subunits of the endosomal sorting complexes required for transport (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 the triggering of self-perpetuating systems are general mechanisms of sequestration-induced proteotoxicity.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 10972765
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198