Parkinson’s disease is a brain disorder that leads to tremors and difficulties with balance and coordination. These symptoms are caused by the loss of neurons which release a chemical messenger that is needed to regulate movement called dopamine. Most treatments for this disease work by boosting levels of dopamine in the brain, but this can lead to severe side effects and these drugs often become less effective over time.

A traditional Chinese medicine called Gastrodia elata Blume (or GE for short) has previously been reported to relieve symptoms of Parkinson’s disease in both human and animal studies when administered as a decoction or formula. However, it is unclear how GE protects dopamine-producing neurons and if this mechanism involves another type of brain cell known as glia that has also been linked to Parkinson’s disease.

To investigate, Lin et al. studied fruit flies and mice that carry a genetic mutation that produces the symptoms and molecular characteristics of Parkinson’s disease. The experiments showed that when the flies and mice were fed food containing water extracts of GE, they experienced less difficulties moving and had a higher number of intact dopamine-producing neurons.

Lin et al. found that GE switched on a protein in glial cells located near dopamine-producing neurons. Activation of this protein, called Nrf2, inhibited a signaling pathway in degenerating neurons that leads to the disease state. As a result, less dopamine-producing neurons were damaged and the animals’ coordination and balance were maintained.

These findings suggest that GE could potentially provide an alternative or complementary therapy for Parkinson’s disease, although it still needs to be studied further in humans. If the same effect is observed, the specific compounds in GE that have this protective effect could be isolated and analyzed to see if they could be used for treatment.

Parkinson’s disease (PD) is a highly prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum of the basal ganglion, representing a circuit involved in motor planning and coordination. As a consequence, PD is associated with motor abnormalities, bradykinesia, hypokinesia, rigidity, and resting tremor. Currently, the most frequently applied pharmacological treatment, levodopa (L-DOPA), exerts limited motor improvement and elicits negative side effects (Ray Chaudhuri et al., 2018). Hence, identifying and developing alternative or complementary treatments may assist in mitigating PD progression.

PD is a multicausal disease with a complicated etiology, including familial inheritance. More than 20 PARK genes have been genetically linked to PD, a number that is increasing (Houlden and Singleton, 2012). Missense mutations in PARK8, or Leucine-rich repeat kinase 2 (LRRK2), induce characteristic PD symptoms and pathologies such as loss of dopaminergic neurons and the appearance of Lewy bodies (Martin et al., 2014). Notably, the most commonly observed mutation, dominant G2019S, among familial PD cases is located in the kinase domain of Lrrk2, which augments its kinase activity via auto- and hyperactivation (Sheng et al., 2012). The hyperactive G2019S mutant protein alters several cellular processes, including vesicle trafficking, microtubule dynamics, autophagy, mitochondrial function (Martin et al., 2014), and, most commonly, increases susceptibility to oxidative stress that contributes to neuronal degeneration (Angeles et al., 2011; Nguyen et al., 2011). These indicate that regulation of the hyperactivation of G2019S mutant protein appears to be a disease-modifying strategy.

Glia provide structural and metabolic supports to neurons and regulate synaptic transmissions, so they are important for the function and survival of dopaminergic neurons (Lin et al., 1993; Sofroniew and Vinters, 2010). Dysfunction in two major glial types, astrocytes and microglia, contribute to the onset and progression of both sporadic and familial PD (Kam et al., 2020). Astrocytes and microglia of postmortem PD brains exhibit pathological lesions and hyper-immunoactivity (Miklossy et al., 2006). A clinical trial involving downregulation of microglial oxidative stress highlights the significance of glia to PD (Jucaite et al., 2015). Moreover, Lrrk2 regulates the inflammatory response in microglia and the autophagy-lysosome pathway in astrocytes, with the G2019S mutation altering the size and pH of lysosomes (Henry et al., 2015; Moehle et al., 2012). Expression of G2019S mutant protein in neurons was previously shown to induce the secretion of Glass bottom boat (Gbb)/bone morphogenetic protein (BMP) signal that, in turn, upregulates Mothers against decapentaplegic (Mad)/Smad signaling in glia, which prompts feedback signals to promote neuronal degeneration (Maksoud et al., 2019). These studies indicate that G2019S mutant protein alters the homeostasis and interaction between neurons and glia, contributing to PD pathogenesis. However, whether any dietary or pharmacological treatment blockading this neuron-glia interaction beneficiary to G2019S-induced PD is unclear.

Given that up to 70% of human PARK genes are conserved in the Drosophila genome, Drosophila is frequently used as a PD model for studying gene function, such as the PARK1/SNCA (Chen and Feany, 2005) and PARK8/LRRK2 (Liu et al., 2008). Genetic and molecular linkage between PINK1/PARK6 and Parkin/PARK2 was first established in Drosophila (Clark et al., 2006). When overexpressed in Drosophila dopaminergic neurons, LRRK2 transgenes carrying G2019S or other dominant mutations induce dopaminergic neuron loss and locomotion impairment, two age-dependent symptoms of PD (Lin et al., 2010; Liu et al., 2008). The G2019S model has further been used to screen a collection of FDA-approved drugs to suppress these PD phenotypes. Thus, Drosophila represents an amenable model of PD for genetic, molecular, and pharmacological study of potential therapeutic interventions. Strikingly, lovastatin was found to prevent dendrite degeneration, dopaminergic neuron loss, and impaired locomotion, and, critically, a lovastatin-involved Nrf2 pathway proved neuroprotective (Lin et al., 2016a). Nevertheless, whether the Nrf2-mediated neuroprotection is cell- or non-cell-autonomous remains elusive.

Traditional Chinese Medicine (TCM) is often used as an alternative or dietary treatment for human diseases, including PD (Kim et al., 2012; Li et al., 2017). Although the results were inconclusive, some TCM could display adjuvant effects when used in combination with L-DOPA, reducing the L-DOPA dosage required in long-term treatments and relieving non-motor symptoms (Kim et al., 2012). As a prominent component in TCM, Gastrodia elata Blume (GE; Orchidaceae) has been used to treat neurological disorders for centuries (Chen and Sheen, 2011). GE has been shown to exert neuroprotective, anti-inflammatory, and antioxidative effects in neurodegenerative disease models (Jang et al., 2015). The major bioactive compounds in GE include gastrodin and 4-hydroxybenzyl alcohol (4-HBA), both of which display pharmacological effects on neurobiological and psychological disorders (Chen et al., 2016; Kumar et al., 2013). Additionally, gastrodin and 4-HBA have been reported to activate the Nrf2 signaling in dopaminergic neurons and astrocytes, respectively (Jiang et al., 2014; Luo et al., 2017), highlighting a potential benefit of incorporating GE in PD treatments. However, the effects and mechanisms underlying how GE moderate Lrrk2-G2019S PD remain unclear.

In the present study, we treated G2019S animals with water extract of GE (WGE), and its bioactive compounds, gastrodin and 4-HBA. We have investigated the impact of WGE treatment on PD in restoring locomotion and protecting dopaminergic neurons in the Drosophila G2019S model. We identified two distinct pathways induced by WGE in the model, that is, suppression of Lrrk2 protein accumulation and hyperphosphorylation in neurons, and activation of the Nrf2 pathway in glia, particularly in astrocyte-like and ensheathing glia. We show that WGE-induced Nrf2 activation antagonizes the Gbb-activated Mad signaling in glia, contributing to neuronal protection. WGE also suppressed the hyperactivation of G2019S proteins and antagonized Smad2/3 signaling in a LRRK2-G2019S mouse model, which restored locomotion, protected dopaminergic neurons, and regulated the microglia hyperactivation. Conservation of the pathways impacted by WGE treatment in both the Drosophila and mouse G2019S models implies the beneficial effects of GE and represent a reliable and effective complementary therapy for PD.

Motor dysfunction in Drosophila neurodegeneration models has been frequently evaluated by means of negative-geotaxis assay that measures the insect innate response. The assay begins with a sudden external stimulation, which initially inhibits spontaneous locomotion but is followed by climbing behavior. The entire response requires motor circuit coordination and muscle tone regulation, two processes that progressively decline with age and that are impacted by neuropathological insults (Grotewiel et al., 2005). In contrast, the open-arena walking assay allows free exploration without disturbance, representing an assay for locomotor activities that can reveal deficits like bradykinesia (Chen et al., 2014). Our G2019S flies exhibited reduced locomotor activity in both assays. Moreover, the G2019S flies also exhibited centrophobism-like behavior in the open arena (Figure 1D). Centrophobism is indicative of emotional abnormalities, such as anxiety and depression, both of which are often associated with PD (Kulisevsky et al., 2008), and was also displayed by the LRRK2-G2019S mice (Figure 9A). WGE treatment suppresses centrophobism in both fly and mouse PD models and has important implications for tackling major symptoms of PD and even non-PD-related depression, as reported for rodent models (Lin et al., 2018; Lin et al., 2016b). Thus, WGE treatment exerts beneficial effects in both of our PD models.

We found that the 0.1% dosage of WGE is optimal in suppressing age-dependent locomotion decline in G2019S flies, with higher and lower doses being less effective (Figure 1A, Figure 1—figure supplement 1B). Although an inverted U-shaped drug response is common, a plausible explanation for the diminished effectiveness of higher doses is that WGE downregulates the day-time but not night-time locomotor activity of flies (Jo et al., 2017). In mice, higher WGE doses have sleep-promoting effects by activating adenosine A₁/A₂A receptors in the ventrolateral preoptic area (Zhang et al., 2012). Thus, dosage level is critical to the beneficial effects of GE in both PD models.

Gastrodin and 4-HBA are considered the principal active components in GE (Zhan et al., 2016). Although both compounds can cross the blood-brain barrier (Wu et al., 2017), the capability of gastrodin to do so is relatively poor compared to aglyconic 4-HBA due to the glucose moiety (Lin et al., 2007). Gastrodin is quickly metabolized to 4-HBA and undetermined metabolites in the brain (Lin et al., 2008), perhaps explaining the lower effectiveness of gastrodin in G2019S flies. However, it is likely that the combination of gastrodin with other components in GE might exert optimal beneficial effects.

Expression of G2019S mutant protein impacts different clusters of dopaminergic neurons in the fly brain that are known for their connectivity and function. Activation of two specific mushroom body (MB)-projection dopaminergic neurons in the PPL1 cluster inhibits climbing performance (Sun et al., 2018). Mutations in the circadian gene Clock (Clk) cause PPL1 dopaminergic neuron degeneration, accelerating impaired age-associated climbing ability (Vaccaro et al., 2017). Dopaminergic neurons in the PPL2 cluster extend processes to the calyx of the MB, which has been linked to climbing activity (Sun et al., 2018). In contrast, PPM3 neurons project to the central complex, activation of which enhances locomotion (Kong et al., 2010). A significant reduction in dopaminergic neurons in the PPM1/2 cluster was only found at week 4 when impaired locomotion of G2019S flies was prominent. In a PD fly model involving SNCA overexpression and aux knockdown, dopaminergic neurons in the PPM1/2 cluster were selectively degenerated and this phenotype was accompanied by impaired locomotion in relatively young adult flies (Song et al., 2017). We postulate that the age-dependent impaired locomotion displayed by G2019S flies could be caused by gradual and differential loss of dopaminergic neurons in these clusters, thereby affecting different aspects of locomotion. However, further study is needed to test that hypothesis.

Expression of the G2019S mutant protein induces Lrrk2 auto- and hyperphosphorylation, as well as protein accumulation, together enhancing cellular Lrrk2 activity and causing aberrant downstream signaling (Sheng et al., 2012). We have shown here that neuronal expression of Lrrk2-G2019S reduced Akt phosphorylation (Figure 4A and B). Consistently, hyperactivated G2019S mutant protein impaired interaction with and phosphorylation of Akt, resulting in compromised signaling and accelerated neurodegeneration (Ohta et al., 2011; Panagiotakopoulou et al., 2020). However, WGE feeding restored downstream Akt signaling by suppressing G2019S mutant protein hyperactivation. Rab10, one of the best-characterized substrates for Lrrk2, mediates several of Lrrk2’s cellular functions (Karayel et al., 2020). In Drosophila, Rab10 and Lrrk2-G2019S synergistically affect the activity of dopaminergic neurons, mediating deficits in movement (Fellgett et al., 2021; Petridi et al., 2020). We have shown that WGE treatment downregulated levels of Lrrk2 accumulation and phosphorylated Rab10 (Figure 3F–H), thus alleviating their synergistic toxicity. Several kinase inhibitors have been developed to block the kinase activity of Lrrk2, including of both wild-type Lrrk2 and the G2019S mutant, which could affect endogenous Lrrk2 activity (Sheng et al., 2012). Instead, WGE treatment modulates the phosphorylation status and protein level of the G2019S mutant but not those of wild-type Lrrk2. The new hydrogen bond created at the Ser²⁰¹⁹ autophosphorylation site may provide a docking site for some chemicals in WGE, representing a possible explanatory mechanism that warrants further study (Lang et al., 2015).

The antioxidation and detoxification factor Nrf2 is a target of Akt activation. Nrf2 phosphorylation and HO-1 expression levels revealed that Nrf2 is inactivated in G2019S flies, but it was activated by WGE treatment (Figure 4C and D). Intriguingly, our genetic data indicate that Nrf2 primarily functions in the glia of G2019S flies, with Nrf2 depletion from glia eliminating the beneficial effects of WGE and glial Nrf2 activation partially substituting for WGE feeding (Figure 5B). Cortical neurons express much lower levels of Nrf2 than astrocytes owing to hypo-acetylation and transcriptional repression of the Nrf2 promoter (Bell et al., 2015). Moreover, neurons express greater amounts of Cullin 3, the scaffold component of the E3 ubiquitin ligase that targets Nrf2 for proteasomal degradation (Jimenez-Blasco et al., 2015). Both those mechanisms render neuronal Nrf2 inert to activation. Nrf2 activation in astrocytes maintains neuronal integrity and function against oxidative insults in response to stress by supplying antioxidants such as glutathione and HO-1 (Kraft et al., 2004; Vargas and Johnson, 2009). Previous study showed that 4-HBA triggers glia to secrete HO-1 via the Nrf2 pathway, protecting neurons from hydrogen peroxide in the primary culture (Luo et al., 2017). In PD models in which wild-type or mutant α-synuclein is overexpressed, activation of neuronal Nrf2 (Barone et al., 2011; Skibinski et al., 2017) or astrocytic Nrf2 (Gan et al., 2012) proved neuroprotective. In a previous study, lovastatin treatment provides neuroprotection in the G2019S-induced PD model, also through the Akt/Nrf2 pathway (Lin et al., 2016b). As activation of neuronal Nrf2 plays a nonconventional role in promoting developmental dendrite pruning (Chew et al., 2021), it remains interesting to further study the cell types that mediate the action of lovastatin. By genetically manipulating the G2019S fly model, we have shown that WGE-induced Nrf2 activation in glia but not in neurons protects dopaminergic neurons from degeneration and ameliorates impaired locomotion.

Astrocyte-like and ensheathing glia are two major types of glia in the Drosophila nervous system, surrounding and also extending long processes into neuropils of the brain. These astrocyte-like glia exhibit a morphology and function similar to those of mammalian astrocytes, including reuptake of neurotransmitters and phagocytosis of neuronal debris (Freeman, 2015; Tasdemir-Yilmaz and Freeman, 2014). Ensheathing glia of varying morphologies encase axonal tracts and neuropils, regulating neuronal excitability and participating in phagocytosis and injury-induced inflammation (Doherty et al., 2009; Otto et al., 2018). Thus, given their proximity to neurons and similar functions, it is not surprising that both types of glia collectively mediate the protective effects of WGE.

Communication between neurons and glia maintains homeostasis, yet also confers the disease state during neurodegeneration. In the Drosophila G2019S model, upregulation of the BMP ligand Gbb in dopaminergic neurons activates Mad/Smad signaling in glia, which promotes neuronal degeneration via a feedback mechanism (Maksoud et al., 2019). Surprisingly, although the number of dopaminergic neurons in the fly brain is relatively small, the upregulated pMad signal spreads throughout the brain (Figure 7B), suggesting that BMP can be disseminated over long distances. In PD patients, higher levels of TGF-β1 have been detected in the striatum and ventricular cerebrospinal fluid (Vawter et al., 1996). Thus, members of the TGF-β1 superfamily such as TGF-β1 and BMP signaling molecules may represent indicators of neuronal degeneration. Accordingly, disrupting the glia-to-neuron feedback mechanism may sustain neuronal survival. In glia, we found that WGE treatment downregulated the pMad levels that had been increased in the G2019S flies (Figure 7A and B). Nrf2 activation in glia also suppressed the enhanced levels of pMad in G2019S flies (Figure 8B and C). Indeed, our genetic assays indicate that the Nrf2 and Mad pathways interact in the glia of G2019S flies. Thus, WGE exerts its beneficial effects by activating Nrf2 to antagonize the Mad activity that would otherwise contribute to the degeneration of dopaminergic neurons. As a transcriptional activator, Nrf2 induces expression of the inhibitory component Smad7 to form inactive Smad complexes (Song et al., 2019) and the phosphatase subunit PPM1A to alter Smad2/3/4 phosphorylation and DNA binding (Lin et al., 2006). Given that these components are conserved in Drosophila, Nrf2 may employ similar pathways to block Mad signaling in glia.

That glial Nrf2 activation protects neurons is evidenced by our observations of enhanced HO-1 expression (Figure 4C) and increased numbers of dopaminergic neurons (Figure 5C and D). These results support that the role of Nrf2 in glia is to induce expression of antioxidation building blocks, such as phase-II detoxification enzymes, and to enhance inflammatory processes (Hirrlinger and Dringen, 2010; Rojo et al., 2010). In a model of fibrosis, TGF-β/Smad2/3 suppressed expression of the ARE-luciferase reporter and glutathione (Ryoo et al., 2014). Moreover, Nrf2 knockdown was shown to reduce expression of the antioxidative enzyme NAD(P)H quinone dehydrogenase 1 (NQO1), thereby elevating cellular oxidative stress and upregulating TGF-β/Smad targeted gene expression (Prestigiacomo and Suter-Dick, 2018). Hence, we propose that WGE promotes Nrf2 activation to antagonize the Smad signaling in glia that is induced by dopaminergic neuron-secreted BMP/Gbb signal during degeneration.

In our study, the LRRK2-G2019S mice show locomotor defects and dopaminergic loss at the age of 11.5 months. A previous study shows only earlier signs of defects, the reduction of the dopamine level and release at the age of 12 months in the LRRK2-G2019S mice (Li et al., 2010), which could be contributed by the genetic background (FVB/NJ vs. C57BL/6J). Nevertheless, we have demonstrated that feeding these mice with WGE rescues their locomotor coordination, suppresses their centrophobism, and recovers their numbers of dopaminergic neurons and hyperactivated microglia (Figure 9 and Figure 10 A – D). Significantly, we found that the activity of the TGF-β/Smad2/3 pathway was elevated in nigrostriatal brain lysates, and this activity was also suppressed by WGE treatment (Figure 10). Collectively, these results from fly and mouse PD models indicate that the effectiveness of WGE is likely mediated through conserved Nrf2/Mad pathways (Figure 11). Our findings contribute to our mechanistic understanding of PD and provide potential therapeutic strategies that incorporate the traditional herbal medicine GE.

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

   1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
   2. Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "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

   Contribution

   Conceptualization, Investigation, Project administration, Resources, Supervision, Validation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8566-7573

3. En-Peng Ho

   Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

   Contribution

   Data curation, Formal analysis, Methodology

   Competing interests

   No competing interests declared

4. Yi-Ci Ke

   Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

   Contribution

   Data curation, Formal analysis, Methodology

   Competing interests

   No competing interests declared

5. Stavroula Petridi

   1. Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
   2. Department of Biology and York Biomedical Research Institute, University of York, York, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

6. Christopher JH Elliott

   Department of Biology and York Biomedical Research Institute, University of York, York, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

7. Lee-Yan Sheen

   Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan

   Contribution

   Conceptualization, Investigation, Resources, Supervision, Validation, Writing – review and editing

   For correspondence

   lysheen@ntu.edu.tw

   Competing interests

   No competing interests declared

8. Cheng-Ting Chien

   1. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
   2. Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan

   Contribution

   Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Validation, Writing – review and editing

   For correspondence

   ctchien@gate.sinica.edu.tw

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7906-7173

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