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

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 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.

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…In LRRK2 mutation mouse models, reactive astrocytes protect neurons through anti-inflammatory functions. Astrocyte activation of Nrf2 inhibited neural degeneration in transgenic mouse models by antagonizing LRRK2 G2019S -induced Mad/Smad signaling (Lin et al, 2021).…”

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

“…GEB could also improve spatial memory and the expression of choline acetyltransferase in animal models of AD [ 30 ]. Water extracts of GEB, gastrodin, and 4-HBA could prevent the locomotion defects and the neuronal loss via glial Nrf2/Mad signaling in PD models of flies and mice [ 31 ]. GEB could also ameliorate the impairment of cholesterol and glucose metabolism and blood flow by improving hepatic insulin signaling in ORX rats [ 32 ].…”

Introduction: Trends, Puzzles, and Hopes for the Future of Healthcare

“…Finally, bridging "alternative" approaches to healthcare with what may be considered "mainstream" disciplines. These approaches could include the effects of different nutritional components and regimens (Guasch-Ferre et al, 2022;Neal et al, 2021), neurofeedback methods for psychiatric conditions (Dudek & Dodell-Feder, 2021), and studying the modes of action of traditional medicines (Lin et al, 2021c;Molimau-Samasoni et al, 2021;Shi et al, 2021).…”