Regulatory pathway of ferroptotic lipid peroxidation and pathogenesis of Parkinson's disease
Yao Yani
Xia Huan
Feng Tingting
Yang Xinling
Abstract：Objective To investigate the regulatory pathway of lipid peroxidation in ferroptosis and the pathogenesis of Parkinson's disease(PD)at animal level.Methods Zebrafish PD model was established by exposure to 200 μmol/L 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).Zebrafish embryo in 48 h after fertilisation were grouped into a control group(n=100),a MPTP group(n=100),and a MPTP+Nomi group(1.5 μg/ml nomifensine,n=100).Behavioral analysis was performed on zebrafish in 5 d after fertilization for movement ability,rate and distance.The expression of α-synuclein and tyrosine hydroxylase in the zebrafish brain was detected by immu-nofluorescence assay to evaluate the activity of dopaminergic neurons(DA).The levels of iron,glutathione(GSH)and lipid peroxidation,which includes catalase(CAT),glutathione peroxidase 4(GPX4),lipid peroxide(LPO),malondialdehyde(MDA)and reactive oxygen species(ROS),were measured to verify whether iron deposition may cause damage to DA through the metabolic regulation mechanism of lipid peroxidation in iron death.Results Compared with the control group,the movement rate and distance were significantly reduced in the MPTP group(P＜0.01),while Nomi treatment obviously increased the movement rate and distance when compared with the MPTP group(P＜0.01).The MPTP group exhibited obvious DA damage in comparison with the control group,and Nomi treatment reversed the damage caused by MPTP.There was no sta-tistical difference in the CAT level in the three group(P＞0.05).The MPTP group had signifi-cantly increased levels of iron,LPO and MDA and decreased levels of GSH and GPX4 when com-pared with the control group(838.18±143.42 vs 478.53±112.58,P＜0.05;1.71±0.11 vs 1.48±0.14,P＜0.05;4.50±0.64 vs 4.23±0.13,P＜0.05;38.93±1.72 vs 45.97±2.32,P＜0.05;0.17±0.03 vs 0.39±0.04,P＜0.05).The MPTP+Nomi group had significantly increased levels of GSH and GPX4 and decreased levels of iron and LPO when compared with the MPTP group(40.79±1.02 vs 38.93±1.72,P＜0.05;0.26±0.05 vs 0.17±0.03,P＜0.05;326.75±110.95 vs 838.18±143.42,P＜0.05;1.01±0.27 vs 1.71±0.11,P＜0.05).The results of the ROS flow cytometry analysis showed that the percentages of ROS positive cells in the control group,MPTP group,and Nomi group were as follows:Histogram:31.6％,46.2％and 31.3％,Scatter plot:62.4％,73.0％and 65.7％,respectively.Conclusion Ferroptosis is found in PD zebrafish induced by MPTP exposure.Our study has clarified at animal level that the damage of DA caused by iron deposition is related to the metabolic mechanism of lipid peroxidation caused by iron death.
Keywords：Parkinson diseasezebrafishferroptosislipid peroxidesdopaminergic neuronsferrop-tosis
Publication Date：2025-06-15
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：5( 793-797 )