The therapeutic effect of quercetin on the transgenic PD drosophila model with LRRK2 mutation / 西安交通大学学报(医学版)

ABSTRACT

Objective: To study the therapeutic effect and mechanism of quercetin on Parkinson's disease (PD) model induced by a leucine-rich repeat kinase 2 (LRRK2) gene mutation. Methods: PD transgenic drosophila model Ddc-Gal4; UAS-LRRK2/G2019S was generated by Gal4/UAS hybridization and selectively expressed G2019S mutant LRRK2 in dopaminergic neurons. PD transgenic drosophila and control were fed with corn medium supplemented with quercetin in 1, 10 and 100 μmol/L for the treatment group, or with standard corn medium in PD model group and blank control group. The life span and locomotor ability were observed and compared between the quercetin treatment group and the PD drosophila model group. The brains of the drosophila were dissected and stained with TH immunofluorescence antibody to observe the survival rate of dopaminergic neurons. The brain tissues were also measured with Western blot to detect the protein expression levels of TH, GCLC, p-LRRK2, and p-p38MAPK. Results: The group treated with 10 μmol/L quercetin showed the best therapeutic effect on the prolongation of life span and improvement of locomotor ability compared with PD transgenic drosophila model without any treatment. The locomotor activity of drosophila was significantly improved at week 6 and the loss of dopaminergic neurons in the brain of the PD model drosophila was effectively diminished by quercetin. Quercetin also significantly lowered the level of phosphorylated LRRK2 in the PD transgenic drosophila compared with the PD model group (P<0.05), indicating the inhibiting effect of quercetin on the activity of LRRK2 kinase of the PD model. In addition, quercetin could activate the antioxidant-signaling pathway and inhibit the p38MAPK signaling pathway. Results: Quercetin can activate the antioxidant-signaling pathway and inhibit the LRRK2 kinase activity, which can further regulate MAPK signaling pathway and reduce the neurotoxicity of LRRK2 mutation and protect dopaminergic neurons in PD transgenic drosophila model.