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

Sitron CS, Trinkaus VA, Galesic A, Garhammer M, Yuste-Checa P, Dransfeld U, Feigenbutz D, Zhang J, Ivashko L, Dudanova I

Mol Cell 2025

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1. Mol Cell. 2025 Sep 18;85(18):3505-3523.e17. doi: 10.1016/j.molcel.2025.08.022. Epub 2025 Sep 10. α-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation. Sitron CS(1), Trinkaus VA(1), Galesic A(2), Garhammer M(1), Yuste-Checa P(1), Dransfeld U(1), Feigenbutz D(3), Zhang J(4), Ivashko L(1), Dudanova I(3), Harper JW(2), Hartl FU(5). Author information: (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: uhartl@biochem.mpg.de. 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. Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.molcel.2025.08.022 PMID: 40934925 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests J.W.H. is a co-founder of Caraway Therapeutics, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and is a member of the scientific advisory board for Lyterian Therapeutics.