IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58618-4.html
   My bibliography  Save this article

Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5

Author

Listed:
  • Zhefan Stephen Chen

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Shaohong Isaac Peng

    (The Chinese University of Hong Kong)

  • Lok I Leong

    (The Chinese University of Hong Kong)

  • Terence Gall-Duncan

    (The Hospital for Sick Children
    University of Toronto)

  • Nathan Siu Jun Wong

    (The Chinese University of Hong Kong)

  • Tsz Ho Li

    (The Chinese University of Hong Kong)

  • Xiao Lin

    (The Chinese University of Hong Kong)

  • Yuming Wei

    (The Chinese University of Hong Kong)

  • Alex Chun Koon

    (The Chinese University of Hong Kong)

  • Junzhe Huang

    (The Chinese University of Hong Kong)

  • Jacquelyne Ka-Li Sun

    (The Chinese University of Hong Kong)

  • Clinton Turner

    (Auckland City Hospital)

  • Lynette Tippett

    (University of Auckland
    University of Auckland)

  • Maurice A. Curtis

    (University of Auckland
    University of Auckland)

  • Richard L. M. Faull

    (University of Auckland
    University of Auckland)

  • Kin Ming Kwan

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Hei-Man Chow

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Ho Ko

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Ting-Fung Chan

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Kevin Talbot

    (University of Oxford
    University of Oxford, Dorothy Crowfoot Hodgkin Building)

  • Christopher E. Pearson

    (The Hospital for Sick Children
    University of Toronto)

  • Ho Yin Edwin Chan

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that play crucial roles in post-transcriptional gene regulation. Poly(A) RNA polymerase D5 (PAPD5) catalyzes the addition of adenosine to the 3′ end of miRNAs. In this study, we demonstrate that the Yin Yang 1 protein, a transcriptional repressor of PAPD5, is recruited to both RNA foci and protein aggregates, resulting in an upregulation of PAPD5 expression in Huntington’s disease (HD). Additionally, we identify a subset of PAPD5-regulated miRNAs with increased adenylation and reduced expression in our disease model. We focus on miR-7-5p and find that its reduction causes the activation of the TAB2-mediated TAK1–MKK4–JNK pro-apoptotic pathway. This pathway is also activated in induced pluripotent stem cell-derived striatal neurons and post-mortem striatal tissues isolated from HD patients. In addition, we discover that a small molecule PAPD5 inhibitor, BCH001, can mitigate cell death and neurodegeneration in our disease models. This study highlights the importance of PAPD5-mediated miRNA dysfunction in HD pathogenesis and suggests a potential therapeutic direction for the disease.

Suggested Citation

  • Zhefan Stephen Chen & Shaohong Isaac Peng & Lok I Leong & Terence Gall-Duncan & Nathan Siu Jun Wong & Tsz Ho Li & Xiao Lin & Yuming Wei & Alex Chun Koon & Junzhe Huang & Jacquelyne Ka-Li Sun & Clinton, 2025. "Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58618-4
    DOI: 10.1038/s41467-025-58618-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58618-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58618-4?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
    ---><---

    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:16:y:2025:i:1:d:10.1038_s41467-025-58618-4. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.