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

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.

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Gastrodia elata Blume prevents dopaminergic neuron degeneration via glial Nrf2 signaling in Lrrk2-G2019S Parkinson's disease models

10.1101/2021.08.25.457612 ◽

2021 ◽

Author(s):

Yu-En Lin ◽

Chin-Hsien Lin ◽

En-Peng Ho ◽

Yi-Ci Ke ◽

Stavroula Petridi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transgenic Mouse ◽

Dopaminergic Neurons ◽

Dopaminergic Neuron ◽

Molecular Mechanisms ◽

Water Extract ◽

Missense Mutations ◽

Gastrodia Elata ◽

G2019s Mutation

Background: Parkinson's disease (PD) remains an incurable neurodegenerative disease. The most frequent missense mutations in familial PD occur in the highly conserved LRRK2/PARK8 gene. Both fly and mouse models of PD carrying the LRRK2 transgene with a dominant G2019S mutation exhibit locomotion defects and loss of dopaminergic neurons. Gastrodia elata Blume (GE) is an herbal medicine traditionally used to treat neurological diseases and 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. Methods: We pharmacologically treated the Drosophila G2019S model with water extract of GE (WGE) to evaluate the neuroprotective and locomotion-improving effects. The biochemical analyses and genetic manipulations were further applied to dissect the potential molecular pathways involved in WGE treatment. We also validated the effects and mechanisms of WGE in a G2019S transgenic mouse model. Results: We show that these G2019S mutant flies fed with WGE showed improved locomotion and stable dopaminergic neurons. WGE suppressed the accumulation and hyperactivation of G2019S mutant protein in dopaminergic neurons, and activated the antioxidation and detoxification factor Nrf2 in glia. Activated Nrf2 antagonizes G2019S-induced Mad/Smad signaling in glia. The effects of WGE on the Drosophila G2019S model were recapitulated in a G2019S transgenic mouse. Conclusion: We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2 upregulation, unveiling a potential therapeutic avenue for PD. Keywords: Parkinson's disease, Lrrk2, Gastrodia elata Blume, Drosophila, dopaminergic neuron, Nrf2, BMP/Mad, glia

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The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease

eLife ◽

10.7554/elife.73062 ◽

2021 ◽

Vol 10 ◽

Author(s):

Aurelie de Rus Jacquet ◽

Jenna L Tancredi ◽

Andrew L Lemire ◽

Michael C DeSantis ◽

Wei-Ping Li ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Extracellular Vesicle ◽

Biological Properties ◽

Neuronal Firing ◽

G2019s Mutation ◽

Lrrk2 G2019s ◽

Induced Pluripotent ◽

Dynamic Relationships

Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson’s disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remain largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes and identify the abnormal accumulation of key PD-related proteins within multivesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs and that LRRK2 G2019S EVs are abnormally enriched in neurites and fail to provide full neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

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The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease

10.1101/2020.07.02.178574 ◽

2020 ◽

Author(s):

Aurelie de Rus Jacquet ◽

Jenna L. Tancredi ◽

Andrew L. Lemire ◽

Michael C. DeSantis ◽

Wei-Ping Li ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Extracellular Vesicle ◽

Biological Properties ◽

Neuronal Firing ◽

G2019s Mutation ◽

Lrrk2 G2019s ◽

Induced Pluripotent ◽

Dynamic Relationships

AbstractAstrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson’s disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remains largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes, generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs but LRRK2 G2019S EVs are abnormally enriched in neurites and provide only marginal neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

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Corynoxine Protects Dopaminergic Neurons Through Inducing Autophagy and Diminishing Neuroinflammation in Rotenone-Induced Animal Models of Parkinson’s Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.642900 ◽

2021 ◽

Vol 12 ◽

Author(s):

Leilei Chen ◽

Yujv Huang ◽

Xing Yu ◽

Jiahong Lu ◽

Wenting Jia ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Models ◽

Dopaminergic Neurons ◽

Cell Model ◽

Neuronal Loss ◽

Motor Dysfunction ◽

Neuroprotective Effects ◽

Drug Candidates ◽

Low Dosage

Recent studies have shown that impairment of autophagy is related to the pathogenesis of Parkinson’s disease (PD), and small molecular autophagy enhancers are suggested to be potential drug candidates against PD. Previous studies identified corynoxine (Cory), an oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.) Jacks, as a new autophagy enhancer that promoted the degradation of α-synuclein in a PD cell model. In this study, two different rotenone-induced animal models of PD, one involving the systemic administration of rotenone at a low dosage in mice and the other involving the infusion of rotenone stereotaxically into the substantia nigra pars compacta (SNpc) of rats, were employed to evaluate the neuroprotective effects of Cory. Cory was shown to exhibit neuroprotective effects in the two rotenone-induced models of PD by improving motor dysfunction, preventing tyrosine hydroxylase (TH)-positive neuronal loss, decreasing α-synuclein aggregates through the mechanistic target of the rapamycin (mTOR) pathway, and diminishing neuroinflammation. These results provide preclinical experimental evidence supporting the development of Cory into a potential delivery system for the treatment of PD.

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

Journal of Parkinson s Disease ◽

10.3233/jpd-202421 ◽

2021 ◽

pp. 1-16

Author(s):

Alison Fellgett ◽

C. Adam Middleton ◽

Jack Munns ◽

Chris Ugbode ◽

David Jaciuch ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Genetic Interaction ◽

In Vitro Assays ◽

Rab Proteins ◽

Circadian Activity ◽

Loss Of Function ◽

Lrrk2 G2019s

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

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Blood Exosomes Have Neuroprotective Effects in a Mouse Model of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3807476 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Ting Sun ◽

Zhe-Xu Ding ◽

Xin Luo ◽

Qing-Shan Liu ◽

Yong Cheng

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Amino Acid ◽

Dopaminergic Neurons ◽

Motor Coordination ◽

Oxidized Lipids ◽

Metabolomic Analysis ◽

Neuroprotective Effects ◽

And Control

Parkinson’s disease (PD) is a common and complex neurodegenerative disease; the pathogenesis of which is still uncertain. Exosomes, nanosized extracellular vesicles, have been suggested to participate in the pathogenesis of PD, but their role is unknown. Here, a metabolomic analysis of serum and brain exosomes showed differentially expressed metabolites between 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride- (MPTP-) induced PD mice and control mice, such as oxidized lipids, vitamins, and cholesterol. These metabolites were enriched in coenzyme, nicotinamide, and amino acid pathways related to PD, and they could be served as preclinical biomarkers. We further found that blood-derived exosomes from healthy volunteers alleviated impaired motor coordination in MPTP-treated mice. Results from immunohistochemistry and western blotting indicated that the loss of dopaminergic neurons in substantia nigra and striatum of PD model mice was rescued by the exosome treatment. The exosome treatment also restored the homeostasis of oxidative stress, neuroinflammation, and cell apoptosis in the model mice. These results suggest that exosomes are important mediators for PD pathogenesis, and exosomes are promising targets for the diagnosis and treatment of PD.

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