Identifying a Comprehensive ceRNA Network to Reveal Novel Targets for the Pathogenesis of Parkinson's Disease

Abstract

Parkinson's disease (PD) is the second commonest progressive neurodegenerative disease worldwide. Increasing evidence reveals that non-coding RNAs play roles in the pathophysiological process of PD. The notion called competing endogenous RNAs (ceRNAs) network is used to describe the roles of non-coding RNAs. According to this theory, long non-coding RNAs (lncRNAs) act as microRNAs (miRNAs) sponges by miRNA response elements or miRNA binding sites to control the availability of endogenous miRNA for binding to their target mRNAs. This study aimed to construct a ceRNA network in PD, which might have the potential to clarify the pathogenesis of PD. We investigated differential expression (DE) lncRNAs and mRNAs in substantia nigra array data GSE7621 between PD patients and healthy controls from the Gene Expression Omnibus database. And we used starBase 2.0 and miRWalk 2.0 databases to predict miRNAs that have interactions with DElncRNAs and DEmRNAs. Based on DElncRNAs, DEmRNAs and predicted miRNAs, two ceRNA networks were constructed. The first one was based on lncRNA-miRNA interactions and miRNA-mRNA interactions that shared the same miRNAs that we predicted, on which function annotation and PPI analysis were performed to identify hub genes. Hereby the second ceRNA network was generated to explore the core section in the first ceRNA network and was validated in external datasets. As a result, we identified 31 DE lncRNAs and 1,828 DEmRNAs, and finally constructed the first ceRNA network associated with PD, including 9 lncRNAs, 18 miRNAs, and 185 mRNAs. mRNAs in the first ceRNA network focused on autophagy, DNA repair and vesicle transport, which were critical pathological processes in PD. Nineteen hub genes in the first ceRNA network identified through PPI analysis, the second ceRNA network was constructed to annotate the core part of the first one. Moreover, the core subnetwork was validated in external datasets, of which several nodes including FBXL7, PTBP2, and lncRNA NEAT1 were verified. In conclusion, a ceRNA network was constructed based on the differential expression profiles of whole substantia nigra tissues of normal and PD patients, and the network was subsequently identified which revealed its association with autophagy, DNA repair and vesicle transport. The core subnetwork of the ceRNA network was identified and validated in external data. Our findings offered novel insights into the roles of ceRNAs in the pathogenesis of PD and provided promising diagnostic biomarkers.

Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases

“…This network consisted of 7 lncRNAs (including XIST, PART1, MCF2L2, NOP14-AS1, LINC00328, LINC00302 and FAM215A), 3 miRNAs (miR-7, miR-133b and miR-433) and 55 mRNAs especially enriched in the GnRH, insulin and MAPK signaling pathways. More recently, Zhang and colleagues [ 113 ] identified a new network in a substantia nigra array from PD patients and matched healthy controls that comprised 9 lncRNAs, 18 miRNAs, and 185 mRNAs functionally related to autophagy, DNA repair and vesicle transport, all critical cellular processes in PD. Based on the most significant relationships, they established a second ceRNA network that was validated using external data.…”

Functional characterization of FBXL7 as a novel player in human cancers

“…In addition, accumulated studies have been shown that FBXL7 regulates various biological processes, including apoptosis [ 16 , 18 , 20 ], proliferation [ 16 , 21 , 22 ], mitochondrial function [ 20 ], epithelial-mesenchymal transition (EMT) [ 23 , 24 ], glucose metabolism [ 25 ], DNA damage [ 26 ], endothelial function [ 27 ], allergic inflammatory response [ 28 , 29 ], embryonic development [ 30 ], planar cell polarity [ 31 , 32 ], and drug resistance [ 33 – 35 ]. Therefore, FBXL7 is involved in various human diseases, including asthma [ 28 , 29 , 36 , 37 ], atopy [ 38 ], Alzheimer’s disease [ 39 ], acute urticaria/angioedema [ 40 ], rheumatoid arthritis [ 41 ], Parkinson’s disease [ 42 ], chronic obstructive pulmonary disease [ 26 ], form-deprivation myopia [ 43 ], and cancer [ 23 , 24 , 35 ]. In this review, we summarize the downstream substrates and upstream regulators of FBXL7 and describe its aberrant expression in human cancers, with emphasis on its emerging roles in the regulation of tumorigenesis and tumor progression.…”

Bioinformatics-Based Analysis of the lncRNA-miRNA-mRNA Network and TF Regulatory Network to Explore the Regulation Mechanism in Spinal Cord Ischemia/Reperfusion Injury

“…Hence, the inhibitory effect of miRNA on mRNA might be canceled when miRNAs is combined with MRE on lncRNA. Recently, accumulating studies have demonstrated that the ceRNA network has become increasingly important in the occurrence and progression of diverse diseases, including cancers, Parkinson’s disease, myocardial ischemia/reperfusion injury, and cerebral infarction ( Zou et al, 2019 ; Qi et al, 2020 ; Zhang R. et al, 2020 ; Zhang X. et al, 2020 ). Nonetheless, few studies of ceRNA network in SCII have been reported ( Liu et al, 2018 ; Qiao et al, 2018 ).…”