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Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1

Author

Listed:
  • Frederick C. Nucifora

    (Johns Hopkins University School of Medicine)

  • Leslie G. Nucifora

    (Johns Hopkins University School of Medicine)

  • Chee-Hoe Ng

    (Danone Nutricia Research)

  • Nicolas Arbez

    (Johns Hopkins University School of Medicine)

  • Yajuan Guo

    (Johns Hopkins University School of Medicine)

  • Elaine Roby

    (Johns Hopkins University School of Medicine)

  • Vered Shani

    (Rappaport Institute of Medical Research, Technion-Israel Institute of Technology)

  • Simone Engelender

    (Rappaport Institute of Medical Research, Technion-Israel Institute of Technology)

  • Dong Wei

    (Johns Hopkins University School of Medicine)

  • Xiao-Fang Wang

    (Johns Hopkins University School of Medicine)

  • Tianxia Li

    (University of Maryland School of Pharmacy)

  • Darren J. Moore

    (Center for Neurodegenerative Science, Van Andel Research Institute)

  • Olga Pletnikova

    (Johns Hopkins University School of Medicine)

  • Juan C. Troncoso

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Akira Sawa

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Ted M. Dawson

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Wanli Smith

    (University of Maryland School of Pharmacy)

  • Kah-Leong Lim

    (Neuroscience and Behavioral Disorders Program, Duke-National University of Singapore Graduate Medical School
    National University of Singapore)

  • Christopher A. Ross

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD.

Suggested Citation

  • Frederick C. Nucifora & Leslie G. Nucifora & Chee-Hoe Ng & Nicolas Arbez & Yajuan Guo & Elaine Roby & Vered Shani & Simone Engelender & Dong Wei & Xiao-Fang Wang & Tianxia Li & Darren J. Moore & Olga , 2016. "Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11792
    DOI: 10.1038/ncomms11792
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    Cited by:

    1. Liam C. Hunt & Vishwajeeth Pagala & Anna Stephan & Boer Xie & Kiran Kodali & Kanisha Kavdia & Yong-Dong Wang & Abbas Shirinifard & Michelle Curley & Flavia A. Graca & Yingxue Fu & Suresh Poudel & Yuxi, 2023. "An adaptive stress response that confers cellular resilience to decreased ubiquitination," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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