The interface of condensates of the hnRNPA1 low complexity domain promotes formation of amyloid fibrils

Linsenmeier, M.; Faltova, L.; Capasso Palmiero, U.; Seiffert, C.; Kueffner, A. M.; Pinotsi, D.; Zhou, J.; Mezzenga, R.; Arosio, P.

doi:10.1101/2022.05.23.493075

bioRxiv · 10.1101/2022.05.23.493075

The interface of condensates of the hnRNPA1 low complexity domain promotes formation of amyloid fibrils

Linsenmeier, M.·Faltova, L.·Capasso Palmiero, U.·Seiffert, C.·Kueffner, A. M.·Pinotsi, D.·Zhou, J.·Mezzenga, R.·Arosio, P.

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Abstract

The maturation of liquid-like protein condensates into amyloid fibrils has been associated with neurodegenerative diseases. Here, we analyze the amyloid formation mediated by condensation of the low-complexity domain of hnRNPA1, a protein involved in Amyotrophic Lateral Sclerosis (ALS). We show that phase separation and fibrillation are connected but distinct processes which are independently mediated by different regions of the protein sequence. By monitoring the spatial and temporal evolution of amyloid formation we demonstrate that the formation of fibrils does not occur homogeneously inside the droplets but is promoted at the interface of the condensates. Consistently, we further show that coating the interface of the droplets with surfactant molecules inhibits fibril formation. Our results indicate that the interface of biomolecular condensates can act as an important catalyst for fibril formation, and therefore could represent a possible therapeutic target against the formation of aberrant amyloids mediated by condensation.

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Linsenmeier, M., Faltova, L., Capasso Palmiero, U., Seiffert, C., Kueffner, A. M., Pinotsi, D., Zhou, J., Mezzenga, R., Arosio, P.. 2022-05-23. The interface of condensates of the hnRNPA1 low complexity domain promotes formation of amyloid fibrils. https://doi.org/10.1101/2022.05.23.493075

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