Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy

Sansevrino, R.; Korobeinikov, A.; Chen, J.-H.; Hoffmann, C.; Le Roy, H.; Ruff, K. M.; Major, A.; Nayak, A.; Brosius, P.; Ekman, A.; He, S.; Chen, M.; Jackson, J.; Aguilar Perez, G.; Wang, H.; Tromm, J. V.; Schneider, G.; Lau, K.; Textoris-Taube, K.; Sinn, L. R.; de Boer, R.; Hofstede, L. T.; Franz, J.; Le Gros, M. A.; Rizzoli, S. O.; Outeiro, T. F.; De Los Rios, P.; Demichev, V.; Muelleder, M.; Ralser, M.; Schmitz, D.; Bano, D.; van den Bogaart, G.; Dai, Y.; Espay, A. J.; Eickholt, B.; Stadelmann, C.; Gopal, P. P.; Pappu, R. V.; Salditt, T.; Larabell, C.; Milovanovic, D.

doi:10.64898/2026.10.09.757996

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bioRxiv · 10.64898/2026.10.09.757996

Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy

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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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Sansevrino, R., Korobeinikov, A., Chen, J.-H., Hoffmann, C., Le Roy, H., Ruff, K. M., Major, A., Nayak, A., Brosius, P., Ekman, A., He, S., Chen, M., Jackson, J., Aguilar Perez, G., Wang, H., Tromm, J. V., Schneider, G., Lau, K., Textoris-Taube, K., Sinn, L. R., de Boer, R., Hofstede, L. T., Franz, J., Le Gros, M. A., Rizzoli, S. O., Outeiro, T. F., De Los Rios, P., Demichev, V., Muelleder, M., Ralser, M., Schmitz, D., Bano, D., van den Bogaart, G., Dai, Y., Espay, A. J., Eickholt, B., Stadelmann, C., Gopal, P. P., Pappu, R. V., Salditt, T., Larabell, C., Milovanovic, D.. 2026-10-15. Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy. https://doi.org/10.64898/2026.10.09.757996

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