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The role of biomolecular condensates in protein aggregation

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Abstract

There is an increasing amount of evidence that biomolecular condensates are linked to neurodegenerative diseases associated with protein aggregation, such as Alzheimer’s disease and amyotrophic lateral sclerosis, although the mechanisms underlying this link remain elusive. In this Review, we summarize the possible connections between condensates and protein aggregation. We consider both liquid-to-solid transitions of phase-separated proteins and the partitioning of proteins into host condensates. We distinguish five key factors by which the physical and chemical environment of a condensate can influence protein aggregation, and we discuss their relevance in studies of protein aggregation in the presence of biomolecular condensates: increasing the local concentration of proteins, providing a distinct chemical microenvironment, introducing an interface wherein proteins can localize, changing the energy landscape of aggregation pathways, and the presence of chaperones in condensates. Analysing the role of biomolecular condensates in protein aggregation may be essential for a full understanding of amyloid formation and offers a new perspective that can help in developing new therapeutic strategies for the prevention and treatment of neurodegenerative diseases.

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Fig. 1: Proteins involved in neurodegenerative diseases are capable of phase separation both in vitro and in vivo.
Fig. 2: Overview of the links between protein aggregation and condensates.
Fig. 3: Protein aggregation is composed of multiple steps, each of which can be altered by condensates.
Fig. 4: Two-phase simulations demonstrate the effects of various factors involved in two-phase protein aggregation.
Fig. 5: Condensate interfaces can promote the formation of protein aggregates.
Fig. 6: Protein conformations inside condensates can expand and lead to altered aggregation, whereas chaperones can prevent aggregation inside condensates.

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Acknowledgements

This work was supported financially by a Vidi grant from the Netherlands Organization for Scientific Research (NWO).

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  1. Institute of Molecules and Materials (IMM), Radboud University, Nijmegen, The Netherlands

    Brent S. Visser, Wojciech P. Lipiński & Evan Spruijt

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Visser, B.S., Lipiński, W.P. & Spruijt, E. The role of biomolecular condensates in protein aggregation. Nat Rev Chem 8, 686–700 (2024). https://doi.org/10.1038/s41570-024-00635-w

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