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Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease

  1. Yu-En Lin
  2. Chin-Hsien Lin
  3. En-Peng Ho
  4. Yi-Ci Ke
  5. Stavroula Petridi
  6. Christopher JH Elliott
  7. Lee-Yan Sheen  Is a corresponding author
  8. Cheng-Ting Chien  Is a corresponding author
  1. Academia Sinica, Taiwan
  2. National Taiwan University Hospital, Taiwan
  3. University of Cambridge, United Kingdom
  4. University of York, United Kingdom
  5. National Taiwan University, Taiwan
Research Article
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Cite this article as: eLife 2021;10:e73753 doi: 10.7554/eLife.73753

Abstract

The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine-Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons, and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

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Author details

  1. Yu-En Lin

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5848-5405
  2. Chin-Hsien Lin

    Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  3. En-Peng Ho

    Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  4. Yi-Ci Ke

    Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  5. Stavroula Petridi

    Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Christopher JH Elliott

    Department of Biology and York Biomedical Research Institute, University of York, York, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Lee-Yan Sheen

    Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan
    For correspondence
    lysheen@ntu.edu.tw
    Competing interests
    The authors declare that no competing interests exist.
  8. Cheng-Ting Chien

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    For correspondence
    ctchien@gate.sinica.edu.tw
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7906-7173

Funding

Ministry of Science and Technology, Taiwan (MOST-108-2311-B-001-039-MY3)

  • Cheng-Ting Chien

Parkinson's UK (grant H1201)

  • Stavroula Petridi
  • Christopher JH Elliott

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were approved by the local ethics committee and the Institutional Animal Care and Use Committee (IACUC) of the National Taiwan University (IACUC approval no. 20180103).

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Publication history

  1. Received: September 9, 2021
  2. Accepted: November 12, 2021
  3. Accepted Manuscript published: November 15, 2021 (version 1)

Copyright

© 2021, Lin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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