IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-47585-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-47585-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-47585-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Michele Vendruscolo & Monika Fuxreiter, 2022. "Protein condensation diseases: therapeutic opportunities," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ashish Joshi & Anuja Walimbe & Anamika Avni & Sandeep K. Rai & Lisha Arora & Snehasis Sarkar & Samrat Mukhopadhyay, 2023. "Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Mónika Gönczi & João M. C. Teixeira & Susana Barrera-Vilarmau & Laura Mediani & Francesco Antoniani & Tamás Milán Nagy & Krisztina Fehér & Zsolt Ráduly & Viktor Ambrus & József Tőzsér & Endre Barta & , 2023. "Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Jing Tao & Yanping Zeng & Bin Dai & Yin Liu & Xiaohan Pan & Li-Qiang Wang & Jie Chen & Yu Zhou & Zuneng Lu & Liwei Xie & Yi Liang, 2023. "Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Steen W. B. Bender & Marcus W. Dreisler & Min Zhang & Jacob Kæstel-Hansen & Nikos S. Hatzakis, 2024. "SEMORE: SEgmentation and MORphological fingErprinting by machine learning automates super-resolution data analysis," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47585-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.