IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42876-1.html
   My bibliography  Save this article

Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model

Author

Listed:
  • Tracy-Shi Zhang Fang

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Yu Sun

    (University of Cambridge, Cambridge Biomedical Campus)

  • Andrew C. Pearce

    (Babraham Research Campus)

  • Simona Eleuteri

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Mark Kemp

    (Babraham Research Campus)

  • Christopher A. Luckhurst

    (Babraham Research Campus)

  • Rachel Williams

    (Babraham Research Campus)

  • Ross Mills

    (Babraham Research Campus)

  • Sarah Almond

    (Babraham Research Campus)

  • Laura Burzynski

    (Babraham Research Campus)

  • Nóra M. Márkus

    (Babraham Research Campus)

  • Christopher J. Lelliott

    (Wellcome Sanger Institute)

  • Natasha A. Karp

    (Wellcome Sanger Institute)

  • David J. Adams

    (Wellcome Sanger Institute)

  • Stephen P. Jackson

    (Babraham Research Campus
    University of Cambridge
    University of Cambridge, Cambridge Biomedical Campus)

  • Jin-Feng Zhao

    (University of Dundee)

  • Ian G. Ganley

    (University of Dundee)

  • Paul W. Thompson

    (Babraham Research Campus)

  • Gabriel Balmus

    (University of Cambridge, Cambridge Biomedical Campus
    Transylvanian Institute of Neuroscience)

  • David K. Simon

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

Abstract

Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.

Suggested Citation

  • Tracy-Shi Zhang Fang & Yu Sun & Andrew C. Pearce & Simona Eleuteri & Mark Kemp & Christopher A. Luckhurst & Rachel Williams & Ross Mills & Sarah Almond & Laura Burzynski & Nóra M. Márkus & Christopher, 2023. "Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42876-1
    DOI: 10.1038/s41467-023-42876-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42876-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42876-1?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. Baris Bingol & Joy S. Tea & Lilian Phu & Mike Reichelt & Corey E. Bakalarski & Qinghua Song & Oded Foreman & Donald S. Kirkpatrick & Morgan Sheng, 2014. "The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy," Nature, Nature, vol. 510(7505), pages 370-375, June.
    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. Su Jin Ham & Heesuk Yoo & Daihn Woo & Da Hyun Lee & Kyu-Sang Park & Jongkyeong Chung, 2023. "PINK1 and Parkin regulate IP3R-mediated ER calcium release," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Thomas M. Goralski & Lindsay Meyerdirk & Libby Breton & Laura Brasseur & Kevin Kurgat & Daniella DeWeerd & Lisa Turner & Katelyn Becker & Marie Adams & Daniel J. Newhouse & Michael X. Henderson, 2024. "Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology," Nature Communications, Nature, vol. 15(1), pages 1-20, 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:14:y:2023:i:1:d:10.1038_s41467-023-42876-1. 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.