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.

1. 1. Angeles DC
   2. Gan BH
   3. Onstead L
   4. Zhao Y
   5. Lim KL
   6. Dachsel J
   7. Melrose H
   8. Farrer M
   9. Wszolek ZK
   10. Dickson DW
   11. Tan EK

   (2011) Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death

   Human Mutation 32:1390–1397.

   https://doi.org/10.1002/humu.21582

   • PubMed
   • Google Scholar
2. 1. Bainton RJ
   2. Tsai LTY
   3. Schwabe T
   4. DeSalvo M
   5. Gaul U
   6. Heberlein U

   (2005) moody encodes two GPCRs that regulate cocaine behaviors and blood-brain barrier permeability in Drosophila

   Cell 123:145–156.

   https://doi.org/10.1016/j.cell.2005.07.029

   • PubMed
   • Google Scholar
3. 1. Barone MC
   2. Sykiotis GP
   3. Bohmann D

   (2011) Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson’s disease

   Disease Models & Mechanisms 4:701–707.

   https://doi.org/10.1242/dmm.007575

   • PubMed
   • Google Scholar
4. 1. Bell KFS
   2. Al-Mubarak B
   3. Martel M-A
   4. McKay S
   5. Wheelan N
   6. Hasel P
   7. Márkus NM
   8. Baxter P
   9. Deighton RF
   10. Serio A
   11. Bilican B
   12. Chowdhry S
   13. Meakin PJ
   14. Ashford MLJ
   15. Wyllie DJA
   16. Scannevin RH
   17. Chandran S
   18. Hayes JD
   19. Hardingham GE

   (2015) Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2

   Nature Communications 6:7066.

   https://doi.org/10.1038/ncomms8066

   • PubMed
   • Google Scholar
5. 1. Chatterjee N
   2. Bohmann D

   (2012) A versatile ΦC31 based reporter system for measuring AP-1 and Nrf2 signaling in Drosophila and in tissue culture

   PLOS ONE 7:e34063.

   https://doi.org/10.1371/journal.pone.0034063

   • PubMed
   • Google Scholar
6. 1. Chen L
   2. Feany MB

   (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease

   Nature Neuroscience 8:657–663.

   https://doi.org/10.1038/nn1443

   • PubMed
   • Google Scholar
7. 1. Chen PJ
   2. Sheen LY

   (2011) Gastrodiae Rhizoma (tiān má): a review of biological activity and antidepressant mechanisms

   Journal of Traditional and Complementary Medicine 1:31–40.

   https://doi.org/10.1016/s2225-4110(16)30054-2

   • PubMed
   • Google Scholar
8. 1. Chen CY
   2. Weng YH
   3. Chien KY
   4. Lin KJ
   5. Yeh TH
   6. Cheng YP
   7. Lu CS
   8. Wang HL

   (2012) G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

   Cell Death and Differentiation 19:1623–1633.

   https://doi.org/10.1038/cdd.2012.42

   • PubMed
   • Google Scholar
9. 1. Chen AY
   2. Wilburn P
   3. Hao X
   4. Tully T

   (2014) Walking deficits and centrophobism in an α-synuclein fly model of Parkinson’s disease

   Genes, Brain, and Behavior 13:812–820.

   https://doi.org/10.1111/gbb.12172

   • PubMed
   • Google Scholar
10. 1. Chen WC
    2. Lai YS
    3. Lin SH
    4. Lu KH
    5. Lin YE
    6. Panyod S
    7. Ho CT
    8. Sheen LY

    (2016) Anti-depressant effects of Gastrodia elata Blume and its compounds gastrodin and 4-hydroxybenzyl alcohol, via the monoaminergic system and neuronal cytoskeletal remodeling

    Journal of Ethnopharmacology 182:190–199.

    https://doi.org/10.1016/j.jep.2016.02.001

    • PubMed
    • Google Scholar
11. 1. Chew LY
    2. Zhang H
    3. He J
    4. Yu F

    (2021) The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling

    Cell Reports 36:109466.

    https://doi.org/10.1016/j.celrep.2021.109466

    • PubMed
    • Google Scholar
12. 1. Chou JS
    2. Chen CY
    3. Chen YL
    4. Weng YH
    5. Yeh TH
    6. Lu CS
    7. Chang YM
    8. Wang HL

    (2014) G2019S) LRRK2 causes early-phase dysfunction of SNpc dopaminergic neurons and impairment of corticostriatal long-term depression in the PD transgenic mouse

    Neurobiology of Disease 68:190–199.

    https://doi.org/10.1016/j.nbd.2014.04.021

    • PubMed
    • Google Scholar
13. 1. Clark IE
    2. Dodson MW
    3. Jiang C
    4. Cao JH
    5. Huh JR
    6. Seol JH
    7. Yoo SJ
    8. Hay BA
    9. Guo M

    (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin

    Nature 441:1162–1166.

    https://doi.org/10.1038/nature04779

    • PubMed
    • Google Scholar
14. 1. Doherty J
    2. Logan MA
    3. Taşdemir OE
    4. Freeman MR

    (2009) Ensheathing glia function as phagocytes in the adult Drosophila brain

    The Journal of Neuroscience 29:4768–4781.

    https://doi.org/10.1523/JNEUROSCI.5951-08.2009

    • PubMed
    • Google Scholar
15. 1. Fellgett A
    2. Middleton CA
    3. Munns J
    4. Ugbode C
    5. Jaciuch D
    6. Wilson LG
    7. Chawla S
    8. Elliott CJH

    (2021) Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

    Journal of Parkinson’s Disease 11:1805–1820.

    https://doi.org/10.3233/JPD-202421

    • PubMed
    • Google Scholar
16. 1. Freeman MR

    (2015) Drosophila Central Nervous System Glia

    Cold Spring Harbor Perspectives in Biology 7:a020552.

    https://doi.org/10.1101/cshperspect.a020552

    • Google Scholar
17. 1. Gan L
    2. Vargas MR
    3. Johnson DA
    4. Johnson JA

    (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model

    The Journal of Neuroscience 32:17775–17787.

    https://doi.org/10.1523/JNEUROSCI.3049-12.2012

    • PubMed
    • Google Scholar
18. 1. Grotewiel MS
    2. Martin I
    3. Bhandari P
    4. Cook-Wiens E

    (2005) Functional senescence in Drosophila melanogaster

    Ageing Research Reviews 4:372–397.

    https://doi.org/10.1016/j.arr.2005.04.001

    • PubMed
    • Google Scholar
19. 1. Henry AG
    2. Aghamohammadzadeh S
    3. Samaroo H
    4. Chen Y
    5. Mou K
    6. Needle E
    7. Hirst WD

    (2015) Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression

    Human Molecular Genetics 24:6013–6028.

    https://doi.org/10.1093/hmg/ddv314

    • PubMed
    • Google Scholar
20. 1. Hirrlinger J
    2. Dringen R

    (2010) The cytosolic redox state of astrocytes: Maintenance, regulation and functional implications for metabolite trafficking

    Brain Research Reviews 63:177–188.

    https://doi.org/10.1016/j.brainresrev.2009.10.003

    • PubMed
    • Google Scholar
21. 1. Houlden H
    2. Singleton AB

    (2012) The genetics and neuropathology of Parkinson’s disease

    Acta Neuropathologica 124:325–338.

    https://doi.org/10.1007/s00401-012-1013-5

    • PubMed
    • Google Scholar
22. 1. Jang JH
    2. Son Y
    3. Kang SS
    4. Bae CS
    5. Kim JC
    6. Kim SH
    7. Shin T
    8. Moon C

    (2015) Neuropharmacological Potential of Gastrodia elata Blume and Its Components

    Evidence-Based Complementary and Alternative Medicine 2015:309261.

    https://doi.org/10.1155/2015/309261

    • PubMed
    • Google Scholar
23. 1. Jiang G
    2. Hu Y
    3. Liu L
    4. Cai J
    5. Peng C
    6. Li Q

    (2014) Gastrodin protects against MPP(+)-induced oxidative stress by up regulates heme oxygenase-1 expression through p38 MAPK/Nrf2 pathway in human dopaminergic cells

    Neurochemistry International 75:79–88.

    https://doi.org/10.1016/j.neuint.2014.06.003

    • PubMed
    • Google Scholar
24. 1. Jimenez-Blasco D
    2. Santofimia-Castaño P
    3. Gonzalez A
    4. Almeida A
    5. Bolaños JP

    (2015) Astrocyte NMDA receptors’ activity sustains neuronal survival through a Cdk5-Nrf2 pathway

    Cell Death and Differentiation 22:1877–1889.

    https://doi.org/10.1038/cdd.2015.49

    • PubMed
    • Google Scholar
25. 1. Jo K
    2. Jeon S
    3. Ahn CW
    4. Han SH
    5. Suh HJ

    (2017) Changes in Drosophila melanogaster Sleep-Wake Behavior Due to Lotus (Nelumbo nucifera) Seed and Hwang Jeong (Polygonatum sibiricum) Extracts

    Preventive Nutrition and Food Science 22:293–299.

    https://doi.org/10.3746/pnf.2017.22.4.293

    • PubMed
    • Google Scholar
26. 1. Jucaite A
    2. Svenningsson P
    3. Rinne JO
    4. Cselényi Z
    5. Varnäs K
    6. Johnström P
    7. Amini N
    8. Kirjavainen A
    9. Helin S
    10. Minkwitz M
    11. Kugler AR
    12. Posener JA
    13. Budd S
    14. Halldin C
    15. Varrone A
    16. Farde L

    (2015) Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson’s disease

    Brain 138:2687–2700.

    https://doi.org/10.1093/brain/awv184

    • PubMed
    • Google Scholar
27. 1. Kam T-I
    2. Hinkle JT
    3. Dawson TM
    4. Dawson VL

    (2020) Microglia and astrocyte dysfunction in parkinson’s disease

    Neurobiology of Disease 144:105028.

    https://doi.org/10.1016/j.nbd.2020.105028

    • PubMed
    • Google Scholar
28. 1. Karayel Ö
    2. Tonelli F
    3. Virreira Winter S
    4. Geyer PE
    5. Fan Y
    6. Sammler EM
    7. Alessi DR
    8. Steger M
    9. Mann M

    (2020) Accurate MS-based Rab10 Phosphorylation Stoichiometry Determination as Readout for LRRK2 Activity in Parkinson’s Disease

    Molecular & Cellular Proteomics 19:1546–1560.

    https://doi.org/10.1074/mcp.RA120.002055

    • PubMed
    • Google Scholar
29. 1. Kim T-H
    2. Cho K-H
    3. Jung W-S
    4. Lee MS
    5. Cookson MR

    (2012) Herbal Medicines for Parkinson’s Disease: A Systematic Review of Randomized Controlled Trials

    PLOS ONE 7:e35695.

    https://doi.org/10.1371/journal.pone.0035695

    • Google Scholar
30. 1. Kong EC
    2. Woo K
    3. Li H
    4. Lebestky T
    5. Mayer N
    6. Sniffen MR
    7. Heberlein U
    8. Bainton RJ
    9. Hirsh J
    10. Wolf FW
    11. Frye MA

    (2010) A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

    PLOS ONE 5:e9954.

    https://doi.org/10.1371/journal.pone.0009954

    • Google Scholar
31. 1. Kraft AD
    2. Johnson DA
    3. Johnson JA

    (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult

    The Journal of Neuroscience 24:1101–1112.

    https://doi.org/10.1523/JNEUROSCI.3817-03.2004

    • PubMed
    • Google Scholar
32. 1. Kulisevsky J
    2. Pagonabarraga J
    3. Pascual-Sedano B
    4. García-Sánchez C
    5. Gironell A
    6. Trapecio Group Study

    (2008) Prevalence and correlates of neuropsychiatric symptoms in Parkinson’s disease without dementia

    Movement Disorders 23:1889–1896.

    https://doi.org/10.1002/mds.22246

    • PubMed
    • Google Scholar
33. 1. Kumar H
    2. Kim I-S
    3. More SV
    4. Kim B-W
    5. Bahk Y-Y
    6. Choi D-K

    (2013) Gastrodin protects apoptotic dopaminergic neurons in a toxin-induced Parkinson’s disease model

    Evidence-Based Complementary and Alternative Medicine 2013:514095.

    https://doi.org/10.1155/2013/514095

    • PubMed
    • Google Scholar
34. 1. Lang CA
    2. Ray SS
    3. Liu M
    4. Singh AK
    5. Cuny GD

    (2015) Discovery of LRRK2 inhibitors using sequential in silico joint pharmacophore space (JPS) and ensemble docking

    Bioorganic & Medicinal Chemistry Letters 25:2713–2719.

    https://doi.org/10.1016/j.bmcl.2015.04.027

    • PubMed
    • Google Scholar
35. 1. Li X
    2. Patel JC
    3. Wang J
    4. Avshalumov MV
    5. Nicholson C
    6. Buxbaum JD
    7. Elder GA
    8. Rice ME
    9. Yue Z

    (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S

    The Journal of Neuroscience 30:1788–1797.

    https://doi.org/10.1523/JNEUROSCI.5604-09.2010

    • PubMed
    • Google Scholar
36. 1. Li X
    2. Zhang Y
    3. Wang Y
    4. Xu J
    5. Xin P
    6. Meng Y
    7. Wang Q
    8. Kuang H

    (2017) The Mechanisms of Traditional Chinese Medicine Underlying the Prevention and Treatment of Parkinson’s Disease

    Frontiers in Pharmacology 8:634.

    https://doi.org/10.3389/fphar.2017.00634

    • PubMed
    • Google Scholar
37. 1. Lin LF
    2. Doherty DH
    3. Lile JD
    4. Bektesh S
    5. Collins F

    (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons

    Science 260:1130–1132.

    https://doi.org/10.1126/science.8493557

    • PubMed
    • Google Scholar
38. 1. Lin X
    2. Duan X
    3. Liang YY
    4. Su Y
    5. Wrighton KH
    6. Long J
    7. Hu M
    8. Davis CM
    9. Wang J
    10. Brunicardi FC
    11. Shi Y
    12. Chen YG
    13. Meng A
    14. Feng XH

    (2006) PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling

    Cell 125:915–928.

    https://doi.org/10.1016/j.cell.2006.03.044

    • PubMed
    • Google Scholar
39. 1. Lin LC
    2. Chen YF
    3. Tsai TR
    4. Tsai TH

    (2007) Analysis of brain distribution and biliary excretion of a nutrient supplement, gastrodin, in rat

    Analytica Chimica Acta 590:173–179.

    https://doi.org/10.1016/j.aca.2007.03.035

    • PubMed
    • Google Scholar
40. 1. Lin LC
    2. Chen YF
    3. Lee WC
    4. Wu YT
    5. Tsai TH

    (2008) Pharmacokinetics of gastrodin and its metabolite p-hydroxybenzyl alcohol in rat blood, brain and bile by microdialysis coupled to LC-MS/MS

    Journal of Pharmaceutical and Biomedical Analysis 48:909–917.

    https://doi.org/10.1016/j.jpba.2008.07.013

    • PubMed
    • Google Scholar
41. 1. Lin CH
    2. Tsai PI
    3. Wu RM
    4. Chien CT

    (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ß

    The Journal of Neuroscience 30:13138–13149.

    https://doi.org/10.1523/JNEUROSCI.1737-10.2010

    • PubMed
    • Google Scholar
42. 1. Lin YE
    2. Lin SH
    3. Chen WC
    4. Ho CT
    5. Lai YS
    6. Panyod S
    7. Sheen LY

    (2016a) Antidepressant-like effects of water extract of Gastrodia elata Blume in rats exposed to unpredictable chronic mild stress via modulation of monoamine regulatory pathways

    Journal of Ethnopharmacology 187:57–65.

    https://doi.org/10.1016/j.jep.2016.04.032

    • PubMed
    • Google Scholar
43. 1. Lin CH
    2. Lin HI
    3. Chen ML
    4. Lai TT
    5. Cao LP
    6. Farrer MJ
    7. Wu RM
    8. Chien CT

    (2016b) Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity

    Human Molecular Genetics 25:1965–1978.

    https://doi.org/10.1093/hmg/ddw068

    • PubMed
    • Google Scholar
44. 1. Lin YE
    2. Chou ST
    3. Lin SH
    4. Lu KH
    5. Panyod S
    6. Lai YS
    7. Ho CT
    8. Sheen LY

    (2018) Antidepressant-like effects of water extract of Gastrodia elata Blume on neurotrophic regulation in a chronic social defeat stress model

    Journal of Ethnopharmacology 215:132–139.

    https://doi.org/10.1016/j.jep.2017.12.044

    • PubMed
    • Google Scholar
45. 1. Lin CH
    2. Tsai PI
    3. Lin HY
    4. Hattori N
    5. Funayama M
    6. Jeon B
    7. Sato K
    8. Abe K
    9. Mukai Y
    10. Takahashi Y
    11. Li Y
    12. Nishioka K
    13. Yoshino H
    14. Daida K
    15. Chen ML
    16. Cheng J
    17. Huang CY
    18. Tzeng SR
    19. Wu YS
    20. Lai HJ
    21. Tsai HH
    22. Yen RF
    23. Lee NC
    24. Lo WC
    25. Hung YC
    26. Chan CC
    27. Ke YC
    28. Chao CC
    29. Hsieh ST
    30. Farrer M
    31. Wu RM

    (2020) Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy

    Brain : A Journal of Neurology 143:3352–3373.

    https://doi.org/10.1093/brain/awaa279

    • PubMed
    • Google Scholar
46. 1. Liu Z
    2. Wang X
    3. Yu Y
    4. Li X
    5. Wang T
    6. Jiang H
    7. Ren Q
    8. Jiao Y
    9. Sawa A
    10. Moran T
    11. Ross CA
    12. Montell C
    13. Smith WW

    (2008) A Drosophila model for LRRK2-linked parkinsonism

    PNAS 105:2693–2698.

    https://doi.org/10.1073/pnas.0708452105

    • PubMed
    • Google Scholar
47. 1. Luo L
    2. Kim S-W
    3. Lee H-K
    4. Kim I-D
    5. Lee H
    6. Lee J-K
    7. Arai K

    (2017) Anti-oxidative effects of 4-hydroxybenzyl alcohol in astrocytes confer protective effects in autocrine and paracrine manners

    PLOS ONE 12:e0177322.

    https://doi.org/10.1371/journal.pone.0177322

    • Google Scholar
48. 1. Madabattula ST
    2. Strautman JC
    3. Bysice AM
    4. O’Sullivan JA
    5. Androschuk A
    6. Rosenfelt C
    7. Doucet K
    8. Rouleau G
    9. Bolduc F

    (2015) Quantitative Analysis of Climbing Defects in a Drosophila Model of Neurodegenerative Disorders

    Journal of Visualized Experiments 100:e52741.

    https://doi.org/10.3791/52741

    • Google Scholar
49. 1. Maksoud E
    2. Liao EH
    3. Haghighi AP

    (2019) A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

    Cell Reports 26:1774–1786.

    https://doi.org/10.1016/j.celrep.2019.01.077

    • PubMed
    • Google Scholar
50. 1. Mao Z
    2. Davis RL

    (2009) Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity

    Frontiers in Neural Circuits 3:5.

    https://doi.org/10.3389/neuro.04.005.2009

    • PubMed
    • Google Scholar
51. 1. Martin I
    2. Kim JW
    3. Dawson VL
    4. Dawson TM

    (2014) LRRK2 pathobiology in Parkinson’s disease

    Journal of Neurochemistry 131:554–565.

    https://doi.org/10.1111/jnc.12949

    • PubMed
    • Google Scholar
52. 1. Miklossy J
    2. Arai T
    3. Guo JP
    4. Klegeris A
    5. Yu S
    6. McGeer EG
    7. McGeer PL

    (2006) LRRK2 expression in normal and pathologic human brain and in human cell lines

    Journal of Neuropathology and Experimental Neurology 65:953–963.

    https://doi.org/10.1097/01.jnen.0000235121.98052.54

    • PubMed
    • Google Scholar
53. 1. Moehle MS
    2. Webber PJ
    3. Tse T
    4. Sukar N
    5. Standaert DG
    6. DeSilva TM
    7. Cowell RM
    8. West AB

    (2012) LRRK2 inhibition attenuates microglial inflammatory responses

    The Journal of Neuroscience 32:1602–1611.

    https://doi.org/10.1523/JNEUROSCI.5601-11.2012

    • PubMed
    • Google Scholar
54. 1. Nguyen HN
    2. Byers B
    3. Cord B
    4. Shcheglovitov A
    5. Byrne J
    6. Gujar P
    7. Kee K
    8. Schüle B
    9. Dolmetsch RE
    10. Langston W
    11. Palmer TD
    12. Pera RR

    (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress

    Cell Stem Cell 8:267–280.

    https://doi.org/10.1016/j.stem.2011.01.013

    • PubMed
    • Google Scholar
55. 1. Ohta E
    2. Kawakami F
    3. Kubo M
    4. Obata F

    (2011) LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson’s disease-associated mutations

    FEBS Letters 585:2165–2170.

    https://doi.org/10.1016/j.febslet.2011.05.044

    • PubMed
    • Google Scholar
56. 1. Otto N
    2. Marelja Z
    3. Schoofs A
    4. Kranenburg H
    5. Bittern J
    6. Yildirim K
    7. Berh D
    8. Bethke M
    9. Thomas S
    10. Rode S
    11. Risse B
    12. Jiang X
    13. Pankratz M
    14. Leimkühler S
    15. Klämbt C

    (2018) The sulfite oxidase Shopper controls neuronal activity by regulating glutamate homeostasis in Drosophila ensheathing glia

    Nature Communications 9:3514.

    https://doi.org/10.1038/s41467-018-05645-z

    • PubMed
    • Google Scholar
57. 1. Panagiotakopoulou V
    2. Ivanyuk D
    3. De Cicco S
    4. Haq W
    5. Arsić A
    6. Yu C
    7. Messelodi D
    8. Oldrati M
    9. Schöndorf DC
    10. Perez M-J
    11. Cassatella RP
    12. Jakobi M
    13. Schneiderhan-Marra N
    14. Gasser T
    15. Nikić-Spiegel I
    16. Deleidi M

    (2020) Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells

    Nature Communications 11:5163.

    https://doi.org/10.1038/s41467-020-18755-4

    • PubMed
    • Google Scholar
58. 1. Petridi S
    2. Middleton CA
    3. Ugbode C
    4. Fellgett A
    5. Covill L
    6. Elliott CJH

    (2020) In Vivo Visual Screen for Dopaminergic Rab ↔ LRRK2-G2019S Interactions in Drosophila Discriminates Rab10 from Rab3

    G3: Genes, Genomes, Genetics 10:1903–1914.

    https://doi.org/10.1534/g3.120.401289

    • PubMed
    • Google Scholar
59. 1. Prestigiacomo V
    2. Suter-Dick L

    (2018) Nrf2 protects stellate cells from Smad-dependent cell activation

    PLOS ONE 13:e0201044.

    https://doi.org/10.1371/journal.pone.0201044

    • PubMed
    • Google Scholar
60. 1. Price A
    2. Manzoni C
    3. Cookson MR
    4. Lewis PA

    (2018) The LRRK2 signalling system

    Cell and Tissue Research 373:39–50.

    https://doi.org/10.1007/s00441-017-2759-9

    • PubMed
    • Google Scholar
61. 1. Ray Chaudhuri K
    2. Poewe W
    3. Brooks D

    (2018) Motor and Nonmotor Complications of Levodopa: Phenomenology, Risk Factors, and Imaging Features

    Movement Disorders 33:909–919.

    https://doi.org/10.1002/mds.27386

    • PubMed
    • Google Scholar
62. 1. Rojo AI
    2. Innamorato NG
    3. Martín-Moreno AM
    4. De Ceballos ML
    5. Yamamoto M
    6. Cuadrado A

    (2010) Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease

    Glia 58:588–598.

    https://doi.org/10.1002/glia.20947

    • PubMed
    • Google Scholar
63. 1. Ryoo I
    2. Ha H
    3. Kwak M-K
    4. Mohanraj R

    (2014) Inhibitory Role of the KEAP1-NRF2 Pathway in TGFβ1-Stimulated Renal Epithelial Transition to Fibroblastic Cells: A Modulatory Effect on SMAD Signaling

    PLOS ONE 9:e93265.

    https://doi.org/10.1371/journal.pone.0093265

    • Google Scholar
64. 1. Sang TK
    2. Chang HY
    3. Lawless GM
    4. Ratnaparkhi A
    5. Mee L
    6. Ackerson LC
    7. Maidment NT
    8. Krantz DE
    9. Jackson GR

    (2007) A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine

    The Journal of Neuroscience 27:981–992.

    https://doi.org/10.1523/JNEUROSCI.4810-06.2007

    • PubMed
    • Google Scholar
65. 1. Sheng Z
    2. Zhang S
    3. Bustos D
    4. Kleinheinz T
    5. Le Pichon CE
    6. Dominguez SL
    7. Solanoy HO
    8. Drummond J
    9. Zhang X
    10. Ding X
    11. Cai F
    12. Song Q
    13. Li X
    14. Yue Z
    15. van der Brug MP
    16. Burdick DJ
    17. Gunzner-Toste J
    18. Chen H
    19. Liu X
    20. Estrada AA
    21. Sweeney ZK
    22. Scearce-Levie K
    23. Moffat JG
    24. Kirkpatrick DS
    25. Zhu H

    (2012) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations

    Science Translational Medicine 4:164ra161.

    https://doi.org/10.1126/scitranslmed.3004485

    • PubMed
    • Google Scholar
66. 1. Skibinski G
    2. Hwang V
    3. Ando DM
    4. Daub A
    5. Lee AK
    6. Ravisankar A
    7. Modan S
    8. Finucane MM
    9. Shaby BA
    10. Finkbeiner S

    (2017) Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis

    PNAS 114:1165–1170.

    https://doi.org/10.1073/pnas.1522872114

    • PubMed
    • Google Scholar
67. 1. Smith RB
    2. Machamer JB
    3. Kim NC
    4. Hays TS
    5. Marqués G

    (2012) Relay of retrograde synaptogenic signals through axonal transport of BMP receptors

    Journal of Cell Science 125:3752–3764.

    https://doi.org/10.1242/jcs.094292

    • PubMed
    • Google Scholar
68. 1. Sofroniew MV
    2. Vinters HV

    (2010) Astrocytes: biology and pathology

    Acta Neuropathologica 119:7–35.

    https://doi.org/10.1007/s00401-009-0619-8

    • PubMed
    • Google Scholar
69. 1. Song L
    2. He Y
    3. Ou J
    4. Zhao Y
    5. Li R
    6. Cheng J
    7. Lin CH
    8. Ho MS

    (2017) Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson’s Disease

    Cell Reports 18:1132–1143.

    https://doi.org/10.1016/j.celrep.2017.01.005

    • PubMed
    • Google Scholar
70. 1. Song MK
    2. Lee JH
    3. Ryoo IG
    4. Lee SH
    5. Ku SK
    6. Kwak MK

    (2019) Bardoxolone ameliorates TGF-β1-associated renal fibrosis through Nrf2/Smad7 elevation

    Free Radical Biology & Medicine 138:33–42.

    https://doi.org/10.1016/j.freeradbiomed.2019.04.033

    • PubMed
    • Google Scholar
71. 1. Sun J
    2. Xu AQ
    3. Giraud J
    4. Poppinga H
    5. Riemensperger T
    6. Fiala A
    7. Birman S

    (2018) Neural Control of Startle-Induced Locomotion by the Mushroom Bodies and Associated Neurons in Drosophila

    Frontiers in Systems Neuroscience 12:6.

    https://doi.org/10.3389/fnsys.2018.00006

    • PubMed
    • Google Scholar
72. 1. Sykiotis GP
    2. Bohmann D

    (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila

    Developmental Cell 14:76–85.

    https://doi.org/10.1016/j.devcel.2007.12.002

    • PubMed
    • Google Scholar
73. 1. Takaesu NT
    2. Hyman-Walsh C
    3. Ye Y
    4. Wisotzkey RG
    5. Stinchfield MJ
    6. O’connor MB
    7. Wotton D
    8. Newfeld SJ

    (2006) dSno facilitates baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2

    Genetics 174:1299–1313.

    https://doi.org/10.1534/genetics.106.064956

    • PubMed
    • Google Scholar
74. 1. Tasdemir-Yilmaz OE
    2. Freeman MR

    (2014) Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons

    Genes & Development 28:20–33.

    https://doi.org/10.1101/gad.229518.113

    • PubMed
    • Google Scholar
75. 1. Vaccaro A
    2. Issa AR
    3. Seugnet L
    4. Birman S
    5. Klarsfeld A

    (2017) Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function

    PLOS Genetics 13:e1006507.

    https://doi.org/10.1371/journal.pgen.1006507

    • PubMed
    • Google Scholar
76. 1. Vargas MR
    2. Johnson JA

    (2009) The Nrf2-ARE cytoprotective pathway in astrocytes

    Expert Reviews in Molecular Medicine 11:e17.

    https://doi.org/10.1017/S1462399409001094

    • PubMed
    • Google Scholar
77. 1. Vawter MP
    2. Dillon-Carter O
    3. Tourtellotte WW
    4. Carvey P
    5. Freed WJ

    (1996) TGFbeta1 and TGFbeta2 concentrations are elevated in Parkinson’s disease in ventricular cerebrospinal fluid

    Experimental Neurology 142:313–322.

    https://doi.org/10.1006/exnr.1996.0200

    • PubMed
    • Google Scholar
78. 1. Wu J
    2. Wu B
    3. Tang C
    4. Zhao J

    (2017) Analytical Techniques and Pharmacokinetics of Gastrodia elata Blume and Its Constituents

    Molecules 22:1137.

    https://doi.org/10.3390/molecules22071137

    • Google Scholar
79. 1. Zhan HD
    2. Zhou HY
    3. Sui YP
    4. Du XL
    5. Wang WH
    6. Dai L
    7. Sui F
    8. Huo HR
    9. Jiang TL

    (2016) The rhizome of Gastrodia elata Blume - An ethnopharmacological review

    Journal of Ethnopharmacology 189:361–385.

    https://doi.org/10.1016/j.jep.2016.06.057

    • PubMed
    • Google Scholar
80. 1. Zhang Y
    2. Li M
    3. Kang R-X
    4. Shi J-G
    5. Liu G-T
    6. Zhang J-J

    (2012) NHBA isolated from Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital-treated mice

    Pharmacology, Biochemistry, and Behavior 102:450–457.

    https://doi.org/10.1016/j.pbb.2012.06.002

    • PubMed
    • Google Scholar

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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