2. Academic Validation
  3. α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation

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

  • Mol Cell. 2025 Sep 18;85(18):3505-3523.e17. doi: 10.1016/j.molcel.2025.08.022.
Cole S Sitron 1,  Victoria A Trinkaus 1,  Ana Galesic 2,  Maximilian Garhammer 1,  Patricia Yuste-Checa 1,  Ulrich Dransfeld 1,  Dennis Feigenbutz 3,  Jiuchun Zhang 4,  Larysa Ivashko 1,  Irina Dudanova 3,  J Wade Harper 2,  F Ulrich Hartl 5
Affiliations

Affiliations

  • 1 Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
  • 2 Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Molecular Neurodegeneration Group, Max Planck Institute for Biological Intelligence, 82152 Martinsried, Germany; Department of Molecules-Signaling-Development, Max Planck Institute for Biological Intelligence, 82152 Martinsried, Germany; Center for Anatomy, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
  • 4 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany. Electronic address: [email protected].
PMID: 40934925 DOI: 10.1016/j.molcel.2025.08.022
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.

Keywords

CHMP2B; ESCRT; ESCRT-III; Parkinson’s disease; aggregation; lysosome; protein aggregate spreading; proteostasis; sequestration; α-synuclein.

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