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

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.

Article and author information

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).

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.

Metrics

  • 2,082
    views
  • 295
    downloads
  • 18
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  8. Cheng-Ting Chien
(2021)
Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease
eLife 10:e73753.
https://doi.org/10.7554/eLife.73753

Share this article

https://doi.org/10.7554/eLife.73753

Further reading

    1. Neuroscience
    Xinlin Hou, Peng Zhang ... Dandan Zhang
    Research Article

    Emotional responsiveness in neonates, particularly their ability to discern vocal emotions, plays an evolutionarily adaptive role in human communication and adaptive behaviors. The developmental trajectory of emotional sensitivity in neonates is crucial for understanding the foundations of early social-emotional functioning. However, the precise onset of this sensitivity and its relationship with gestational age (GA) remain subjects of investigation. In a study involving 120 healthy neonates categorized into six groups based on their GA (ranging from 35 and 40 weeks), we explored their emotional responses to vocal stimuli. These stimuli encompassed disyllables with happy and neutral prosodies, alongside acoustically matched nonvocal control sounds. The assessments occurred during natural sleep states using the odd-ball paradigm and event-related potentials. The results reveal a distinct developmental change at 37 weeks GA, marking the point at which neonates exhibit heightened perceptual acuity for emotional vocal expressions. This newfound ability is substantiated by the presence of the mismatch response, akin to an initial form of adult mismatch negativity, elicited in response to positive emotional vocal prosody. Notably, this perceptual shift’s specificity becomes evident when no such discrimination is observed in acoustically matched control sounds. Neonates born before 37 weeks GA do not display this level of discrimination ability. This developmental change has important implications for our understanding of early social-emotional development, highlighting the role of gestational age in shaping early perceptual abilities. Moreover, while these findings introduce the potential for a valuable screening tool for conditions like autism, characterized by atypical social-emotional functions, it is important to note that the current data are not yet robust enough to fully support this application. This study makes a substantial contribution to the broader field of developmental neuroscience and holds promise for future research on early intervention in neurodevelopmental disorders.

    1. Neuroscience
    Luis Alberto Bezares Calderón, Réza Shahidi, Gáspár Jékely
    Research Article

    Hydrostatic pressure is a dominant environmental cue for vertically migrating marine organisms but the physiological mechanisms of responding to pressure changes remain unclear. Here, we uncovered the cellular and circuit bases of a barokinetic response in the planktonic larva of the marine annelid Platynereis dumerilii. Increased pressure induced a rapid, graded, and adapting upward swimming response due to the faster beating of cilia in the head multiciliary band. By calcium imaging, we found that brain ciliary photoreceptors showed a graded response to pressure changes. The photoreceptors in animals mutant for ciliary opsin-1 had a smaller sensory compartment and mutant larvae showed diminished pressure responses. The ciliary photoreceptors synaptically connect to the head multiciliary band via serotonergic motoneurons. Genetic inhibition of the serotonergic cells blocked pressure-dependent increases in ciliary beating. We conclude that ciliary photoreceptors function as pressure sensors and activate ciliary beating through serotonergic signalling during barokinesis.