Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson’s disease
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This study elucidates the molecular mechanisms whereby Gastrodia elata Blume confers neuroprotection in G2019S-induced PD models and provides a potential therapeutic treatment for PD patients. The experiments are very well designed; the images are of high-quality and convincing. The conclusions are well supported by multiple of lines of genetic and biochemical evidence. This is an important and innovative study.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
This article has been Reviewed by the following groups
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
- Evaluated articles (eLife)
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 that 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.
Article activity feed
-
-
Evaluation Summary:
This study elucidates the molecular mechanisms whereby Gastrodia elata Blume confers neuroprotection in G2019S-induced PD models and provides a potential therapeutic treatment for PD patients. The experiments are very well designed; the images are of high-quality and convincing. The conclusions are well supported by multiple of lines of genetic and biochemical evidence. This is an important and innovative study.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
-
Reviewer #1 (Public Review):
In this manuscript Lin et al. report the effect of a Traditional Chinese Medicine, the water extracts of GE (WGE), to suppress neurodegeneration in LRRK2-G2019S flies. They argue that WGE suppresses the accumulation and hyperactivation of LRRK2-G2019S proteins in dopaminergic neurons. WGE also activates the antioxidation and detoxification factor Nrf2 in astrocyte-like and ensheathing glia. This in turn antagonizes LRRK2-G2019S-induced Mad/Smad activation in the glia. Moreover, the authors show that the role of WGE to suppress the hyperactivation of LRRK2-G2019S proteins and regulates Smad2/3 pathway are evolutionally conserved in the brain of the LRRK2-G2019S transgenic mice. Furthermore, WGE also suppresses the locomotion declines, the loss of dopaminergic neurons, and the up-regulation of the number of …
Reviewer #1 (Public Review):
In this manuscript Lin et al. report the effect of a Traditional Chinese Medicine, the water extracts of GE (WGE), to suppress neurodegeneration in LRRK2-G2019S flies. They argue that WGE suppresses the accumulation and hyperactivation of LRRK2-G2019S proteins in dopaminergic neurons. WGE also activates the antioxidation and detoxification factor Nrf2 in astrocyte-like and ensheathing glia. This in turn antagonizes LRRK2-G2019S-induced Mad/Smad activation in the glia. Moreover, the authors show that the role of WGE to suppress the hyperactivation of LRRK2-G2019S proteins and regulates Smad2/3 pathway are evolutionally conserved in the brain of the LRRK2-G2019S transgenic mice. Furthermore, WGE also suppresses the locomotion declines, the loss of dopaminergic neurons, and the up-regulation of the number of the hyperactive microglia in the LRRK2-G2019S transgenic mice.
In summary, the authors provide compelling genetic, biochemical and behavioral data to reveal the function and the mechanism of WGE and its bioactive compounds, gastrodin and 4-HBA, to suppress neurodegenerative phenotypes in two LRRK2-R2019S animal models (flies and mice). Given that the function of WGE is evolutionally conserved in flies and the brain of mice, their data suggest that WGE and its bioactive compounds can be potential therapeutic drugs for PD. Moreover, this manuscript is well written and the authors provide sufficient data to support most of their arguments.
-
Reviewer #2 (Public Review):
In this study, Lin et al. utilized a well-established fly model of Parkinson's disease (PD) carrying the LRRK2-G2019S mutation to demonstrate the mechanisms underlying the neuroprotective effects of Gastrodia elata (GE). They found that G2019S flies treated with water extracts of GE (WGE) or its bioactive components (Gastrodin and 4-HBA) exhibited an improvement in locomotion as well as protection of dopaminergic neurons. They then continued to elucidate the mechanisms of WGE beneficial effects in PD flies. WGE exerts its function via two distinct modes. First, it downregulates the total and active forms of G2019S proteins in dopaminergic neurons. Second, as nicely demonstrated by the use of reporters and tissue-specific drivers, WGE activates the antioxidant factor Nrf2 in the astrocyte-like and ensheathing …
Reviewer #2 (Public Review):
In this study, Lin et al. utilized a well-established fly model of Parkinson's disease (PD) carrying the LRRK2-G2019S mutation to demonstrate the mechanisms underlying the neuroprotective effects of Gastrodia elata (GE). They found that G2019S flies treated with water extracts of GE (WGE) or its bioactive components (Gastrodin and 4-HBA) exhibited an improvement in locomotion as well as protection of dopaminergic neurons. They then continued to elucidate the mechanisms of WGE beneficial effects in PD flies. WGE exerts its function via two distinct modes. First, it downregulates the total and active forms of G2019S proteins in dopaminergic neurons. Second, as nicely demonstrated by the use of reporters and tissue-specific drivers, WGE activates the antioxidant factor Nrf2 in the astrocyte-like and ensheathing glia, rather than in dopaminergic neurons. Activation of Nrf2 is essential for the antagonization of G2019S-induced Mad/Smad signaling in glia. Importantly, the findings from the fly model are applicable to the mouse G2019S model, and similar pathways were implicated in WGE-treated mice. LRRK2-G2019S transgenic mice treated with WGE also show reductions in activation of G2019S proteins and Smad2/3 pathways. This study elucidates the molecular mechanisms whereby GE confers neuroprotection in G2019S-induced PD and provides a potential therapeutic treatment for PD patients. The experiments were very well designed; the images are high-quality and convincing. The conclusions are well supported by multiple of lines of genetic and biochemical evidence. It is a pleasure to read this beautiful manuscript.
-
