Idebenone-Activating Autophagic Degradation of α-Synuclein via Inhibition of AKT-mTOR Pathway in a SH-SY5Y-A53T Model of Parkinson's Disease: A Network Pharmacological Approach.

Pei Kun He,Yu Yuan Gao,Li Min Wang,Kun Nie,Li Juan Wang,Qing Xi Zhang,Qing Rui Duan,Gui Xian Ma,Zhi Hua Liu,Yu Hu Zhang,Rui Huang,He Ling Huang,Feng-Juan Lyu,Jia Ning Chen,Man Li Guo,Jeong June Choi

doi:10.1155/2021/8548380

Abstract

Background Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, which currently lacks disease-modifying therapy to slow down its progression. Idebenone, a coenzyme Q10 (CQ10) analogue, is a well-known antioxidant and has been used to treat neurological disorders. However, the mechanism of Idebenone on PD has not been fully elucidated. This study aims to predict the potential targets of Idebenone and explore its therapeutic mechanism against PD. Method We obtained potential therapeutic targets through database prediction, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Next, we constructed and analyzed a protein-protein interaction network (PPI) and a drug-target-pathway-disease network. A molecular docking test was conducted to identify the interactions between Idebenone and potential targets. Lastly, a PD cell line of SH-SY5Y overexpressing mutant α-synuclein was used to validate the molecular mechanism. Result A total of 87 targets were identified based on network pharmacology. The enrichment analysis highlighted manipulation of MAP kinase activity and the PI3K-AKT signaling pathway as potential pharmacological targets for Idebenone against PD. Additionally, molecular docking showed that AKT and MAPK could bind tightly with Idebenone. In the cell model of PD, Idebenone activated autophagy and promoted α-synuclein degradation by suppressing the AKT/mTOR pathway. Pretreating cells with chloroquine (CQ) to block autophagic flux could diminish the pharmacological effect of Idebenone to clear α-synuclein. Conclusion This study demonstrated that Idebenone exerts its anti-PD effects by enhancing autophagy and clearance of α-synuclein, thus providing a theoretical and experimental basis for Idebenone therapy against PD.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease, whose prevalence is growing faster than any other neurological disorder [1]
A Venn diagram showing the common 87 targets between PD and Idebenone is shown in Figure 1(b), and the details of the 87 genes are presented in Supplementary Table S3
To identify the function of the potential targets, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the 87 target genes. e GO analysis included biological process (BP), cellular component (CC), and molecular function (MF). e top 20 most significant terms are shown in Figures 2(a)–2(c) (Table S4). e main biological process included peptidylserine phosphorylation, positive regulation of protein serine/threonine kinase activity, calcium ion homeostasis, positive regulation of MAP kinase, and positive regulation of reactive oxygen species metabolic process. e cellular components involved include neuronal cell body, integral component of presynaptic membrane, membrane raft, presynaptic membrane, and perikaryon. e main molecular functions included protein serine/threonine kinase activity, MAP kinase activity, phosphatidylinositol 3-kinase activity, protein phosphatase binding, and insulin receptor substrate binding

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, whose prevalence is growing faster than any other neurological disorder [1]. Idebenone may not act as a direct antioxidant according to its pharmacological kinetics and instead exerts cytoprotective effects via numerous physiological mechanisms, including inhibition of P52Shc, increasing the expression of Lin28A, and regulation of AKT [6]. Is study aims to predict the potential targets of Idebenone and explore its therapeutic mechanism against PD. We constructed and analyzed a protein-protein interaction network (PPI) and a drug-target-pathway-disease network. A molecular docking test was conducted to identify the interactions between Idebenone and potential targets. E enrichment analysis highlighted manipulation of MAP kinase activity and the PI3K-AKT signaling pathway as potential pharmacological targets for Idebenone against PD. In the cell model of PD, Idebenone activated autophagy and promoted α-synuclein degradation by suppressing the AKT/mTOR pathway. Conclusion. is study demonstrated that Idebenone exerts its anti-PD effects by enhancing autophagy and clearance of α-synuclein, providing a theoretical and experimental basis for Idebenone therapy against PD

Methods

Results

Conclusion