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

Yu-En Lin,Cheng-Ting Chien,Stavroula Petridi,Chin-Hsien Lin,Christopher Jh Elliott,Yi-Ci Ke,Lee-Yan Sheen,En-Peng Ho

doi:10.7554/elife.73753

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.

Highlights

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
We have investigated the impact of water extract of GE (WGE) treatment on PD in restoring locomotion and protecting dopaminergic neurons in the Drosophila G2019S model
Numbers of dopaminergic neurons in the PPL1 cluster were reduced upon glial 300 overexpression of Mothers against decapentaplegic (Mad) or tkvQ253D and they were restored by 0.1% WGE treatment (Figure 7E to H). These analyses indicate that activation of bone morphogenetic protein (BMP) signaling in glia recapitulates the phenotypes observed in flies overexpressing G2019S mutant protein in dopaminergic neurons and, that these effects can be suppressed by WGE treatment

Summary

Introduction

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. PD is associated with motor abnormalities, bradykinesia, hypokinesia, rigidity and resting tremor. The most frequently applied pharmacological treatment, levodopa (L-DOPA), exerts limited motor improvement and elicits negative side-effects (Ray Chaudhuri et al, 2018). Identifying and developing alternative or complementary treatments may assist in mitigating PD progression. PD is a multi-causal disease with a complicated etiology, including familial inheritance.

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