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Pharmacological inhibition of α-synuclein aggregation within liquid condensates

Author

Listed:
  • Samuel T. Dada

    (University of Cambridge)

  • Zenon Toprakcioglu

    (University of Cambridge)

  • Mariana P. Cali

    (University of Cambridge)

  • Alexander Röntgen

    (University of Cambridge)

  • Maarten C. Hardenberg

    (University of Cambridge)

  • Owen M. Morris

    (University of Cambridge)

  • Lena K. Mrugalla

    (University of Cambridge)

  • Tuomas P. J. Knowles

    (University of Cambridge)

  • Michele Vendruscolo

    (University of Cambridge)

Abstract

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson’s disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson’s disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson’s disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.

Suggested Citation

  • Samuel T. Dada & Zenon Toprakcioglu & Mariana P. Cali & Alexander Röntgen & Maarten C. Hardenberg & Owen M. Morris & Lena K. Mrugalla & Tuomas P. J. Knowles & Michele Vendruscolo, 2024. "Pharmacological inhibition of α-synuclein aggregation within liquid condensates," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47585-x
    DOI: 10.1038/s41467-024-47585-x
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    References listed on IDEAS

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    1. Michele Vendruscolo & Monika Fuxreiter, 2022. "Protein condensation diseases: therapeutic opportunities," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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