Figure 11. The proposed model of water extract of Gastrodia elata Blume (WGE) in the G2019S-induced neurodegeneration.

Accumulation of the hyperactivated G2019S mutant protein enhances the BMP ligand (Gbb) maturation via upregulation of Furin 1 translation in dopaminergic neurons. Secreted Gbb binds to the BMP receptor, Tkv, and turns on Mad signaling in glia. The G2019S mutation also decreases the Nrf2 activity in the brain, particularly in glia. Both upregulated Mad and downregulated Nrf2 pathways contribute to neurodegeneration. WGE feeding suppresses G2019S hyperactivation in neurons and restores Nrf2 activity mostly in the astrocyte-like and ensheathing glia. WGE-elevated Nrf2 activity in glia antagonizes the BMP/Mad signaling and initiates Nrf2/HO-1 axis in glia, attenuating the stress signals from glia and promoting neuroprotection. Red and green solid arrows (→) indicate the observed effects exerted by G2019S overexpression and WGE feeding, respectively, in the present study. Red and green dashed arrows (-->) indicate the proposed actions trigged by Mad signaling and WGE feeding, respectively. Red and green blunt-ended lines (---|) indicate the proposed inhibitions by Mad and Nrf2 overexpression, respectively. (P) Indicates phosphorylation. The Furin 1-mediated Gbb pathway labeled in gray is modified from Figure 6 of Maksoud et al., 2019.