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

Sitron, C. S.; Trinkaus, V. A.; Galesic, A. G.; Garhammer, M.; Yuste Checa, P.; Dransfeld, U.; Feigenbutz, D.; Zhang, J.; Dudanova, I.; Harper, J. W.; Hartl, F. U.

doi:10.1101/2025.01.13.632710

bioRxiv · 10.1101/2025.01.13.632710

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

Sitron, C. S.·Trinkaus, V. A.·Galesic, A. G.·Garhammer, M.·Yuste Checa, P.·Dransfeld, U.·Feigenbutz, D.·Zhang, J.·Dudanova, I.·Harper, J. W.·Hartl, F. U.

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Abstract

-Synuclein aggregation is a hallmark of Parkinsons disease and related synucleinopathies. Extracellular -synuclein fibrils enter naive cells via endocytosis, followed by transit into the cytoplasm to seed endogenous -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 -synuclein fibrils interact with an -helix common to ESCRT-III proteins. This interaction results in sequestration of 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, which in turn increases aggregation and ESCRT-III sequestration. We suggest that collateral degradation and triggering of self-perpetuating systems could be general mechanisms of sequestration-induced proteotoxicity. HIGHLIGHTSO_LI-Synuclein fibrils bind and sequester ESCRT-III endolysosome repair proteins C_LIO_LIAn -helical segment common to ESCRT-III mediates fibril-selective interaction C_LIO_LIFibril-bound ESCRT-III subunits undergo "collateral degradation" via the proteasome C_LIO_LIESCRT-III depletion damages endolysosomes and worsens -synuclein aggregation C_LI

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Sitron, C. S., Trinkaus, V. A., Galesic, A. G., Garhammer, M., Yuste Checa, P., Dransfeld, U., Feigenbutz, D., Zhang, J., Dudanova, I., Harper, J. W., Hartl, F. U.. 2025-01-13. Alpha-Synuclein aggregates inhibit ESCRT-III through sequestration and collateral degradation. https://doi.org/10.1101/2025.01.13.632710

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