Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy
- 1Charite - Berlin University Medicine
Abstract
Understanding how soluble monomeric alpha-synuclein transitions into pathological alpha-synuclein (Lewy bodies) has remained a central challenge in neurodegeneration. Existing models, largely based on treating cells and animals with pre-formed alpha-synuclein fibrils cannot account for the emergence of the first inclusion without pre-existing seeds. Here, we combine in vitro reconstitutions, computational modeling and a minimal cellular system to show that phase separation of alpha-synuclein with an interacting scaffold can recapitulate Lewy body-like structures. An unbiased proteomics screen, live-cell imaging, correlative light-electron microscopy, and soft X-ray tomography show that Lewy body-like structures are associated with redistribution of actin and membrane-bound organelles, with mitochondria accumulating at their periphery in an actin-dependent manner. Structural analyses further indicate that alpha-synuclein condensates provide local environments in which the insoluble beta-sheets can form. Together, these findings support a seed-independent trajectory from soluble alpha-synuclein through condensation and progressive immobilization to Lewy body-like assemblies and, subsequently, insoluble beta-sheet fibrils. This framework offers a new mechanistic route for understanding the disease progression and promises to guide the design of innovative therapeutic interventions.
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BibTeX
@misc{sansevrino2026reverse,
title = {{Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy}},
author = {R. Sansevrino and A. Korobeinikov and J.-H. Chen and C. Hoffmann and H. Le Roy and K. M. Ruff and A. Major and A. Nayak and P. Brosius and A. Ekman and S. He and M. Chen and J. Jackson and G. Aguilar Perez and H. Wang and J. V. Tromm and G. Schneider and K. Lau and K. Textoris-Taube and L. R. Sinn and R. de Boer and L. T. Hofstede and J. Franz and M. A. Le Gros and S. O. Rizzoli and T. F. Outeiro and P. De Los Rios and V. Demichev and M. Muelleder and M. Ralser and D. Schmitz and D. Bano and G. van den Bogaart and Y. Dai and A. J. Espay and B. Eickholt and C. Stadelmann and P. P. Gopal and R. V. Pappu and T. Salditt and C. Larabell and D. Milovanovic},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.757996},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757996v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy
AU - R. Sansevrino
AU - A. Korobeinikov
AU - J.-H. Chen
AU - C. Hoffmann
AU - H. Le Roy
AU - K. M. Ruff
AU - A. Major
AU - A. Nayak
AU - P. Brosius
AU - A. Ekman
AU - S. He
AU - M. Chen
AU - J. Jackson
AU - G. Aguilar Perez
AU - H. Wang
AU - J. V. Tromm
AU - G. Schneider
AU - K. Lau
AU - K. Textoris-Taube
AU - L. R. Sinn
AU - R. de Boer
AU - L. T. Hofstede
AU - J. Franz
AU - M. A. Le Gros
AU - S. O. Rizzoli
AU - T. F. Outeiro
AU - P. De Los Rios
AU - V. Demichev
AU - M. Muelleder
AU - M. Ralser
AU - D. Schmitz
AU - D. Bano
AU - G. van den Bogaart
AU - Y. Dai
AU - A. J. Espay
AU - B. Eickholt
AU - C. Stadelmann
AU - P. P. Gopal
AU - R. V. Pappu
AU - T. Salditt
AU - C. Larabell
AU - D. Milovanovic
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.757996
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.757996v1
AB - Understanding how soluble monomeric alpha-synuclein transitions into pathological alpha-synuclein (Lewy bodies) has remained a central challenge in neurodegeneration. Existing models, largely based on treating cells and animals with pre-formed alpha-synuclein fibrils cannot account for the emergence of the first inclusion without pre-existing seeds. Here, we combine in vitro reconstitutions, computational modeling and a minimal cellular system to show that phase separation of alpha-synuclein with an interacting scaffold can recapitulate Lewy body-like structures. An unbiased proteomics screen, live-cell imaging, correlative light-electron microscopy, and soft X-ray tomography show that Lewy body-like structures are associated with redistribution of actin and membrane-bound organelles, with mitochondria accumulating at their periphery in an actin-dependent manner. Structural analyses further indicate that alpha-synuclein condensates provide local environments in which the insoluble beta-sheets can form. Together, these findings support a seed-independent trajectory from soluble alpha-synuclein through condensation and progressive immobilization to Lewy body-like assemblies and, subsequently, insoluble beta-sheet fibrils. This framework offers a new mechanistic route for understanding the disease progression and promises to guide the design of innovative therapeutic interventions.
ER -