Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson’s Disease in a Mouse Model

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease and although many studies have been done on this disease, the underlying mechanisms are still poorly understood and further studies are warranted. Therefore, this study identified circRNA expression profiles in the cerebral cortex (CC), hippocampus (HP), striatum (ST), and cerebellum (CB) regions of the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model using RNA sequencing (RNA-seq), and differentially expressed circRNA were validated using reverse transcription quantitative real-time PCR (qRT-PCR). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analyses were also performed to explore the potential function of circRNAs. The results show that, compared with the control group, 24, 66, 71, and 121 differentially expressed circRNAs (DE-circRNAs) were found in the CC, HP, ST, and CB, respectively. PDST vs. PDCB, PDST vs. PDHP, and PDCB vs. PDHP groups have 578, 110, and 749 DE-circRNAs, respectively. Then, seven DE-cirRNAs were selected for qRT-PCR verification, where the expressions were consistent with the sequencing analysis. The GO and KEGG pathway analyses revealed that these DE-circRNAs participate in several biological functions and signaling pathways, including glutamic synapse, neuron to neuron synapse, cell morphogenesis involved in neuron differentiation, Parkinson’s disease, axon guidance, cGMP-PKG signaling pathway, and PI3K-Akt signaling pathway. Furthermore, the KEGG analysis of the target genes predicted by DE-circRNAs indicated that the target genes predicted by mmu_circRNA_0003292, mmu_circRNA_0001320, mmu_circRNA_0005976, and mmu_circRNA_0005388 were involved in the PD-related pathway. Overall, this is the first study on the expression profile of circRNAs in the different brain regions of PD mouse model. These results might facilitate our understanding of the potential roles of circRNAs in the pathogenesis of PD. Moreover, the results also indicate that the mmu_circRNA_0003292-miRNA-132-Nr4a2 pathway might be involved in the regulation of the molecular mechanism of Parkinson’s disease.

Non-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease

“…Further, a circRNA transcriptome profiling study from different brain regions of MPTP-induced PD mouse model revealed differential expression of six circRNAs predicted to be involved in the PD-related pathways. Through an in silico analysis, mmu-circRNA-0003292, and mmu_circRNA_0001320 were predicted to interact with well-known PD-related miRNAs, miR-132, and miR-124, respectively [150]. A recent study on RNA sequencing of brain samples from PD patients and controls also showed the presence of differentially expressed circRNAs in different brain regions.…”

Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era

“…222,226,227 miR-132 regulates embryonic stem cell differentiation into dopaminergic cells, while miR-132 was upregulated in a PD mouse model and reduced dopamine neuron differentiation. The miRNA sponge mmu-circRNA-0003292 is hypothesized to sequester miR-132 and affect PD pathogenesis, 228 however, further experimental verification is needed.…”

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

“…In addition, CircSLC8A1 expression was sensitive to OS status in culture cells, overall suggesting an OS-mediated deregulation of the CircSLC8A1/miR-128 pathway in PD. circRNAs have also been shown to be deregulated in multiple brain regions in the MPTP mouse model of PD [205]. The enrichment pathway analysis of deregulated circRNAs highlighted diverse biological functions, including synapse function, neuronal differentiation, axon guidance and PD metabolism.…”

“…The enrichment pathway analysis of deregulated circRNAs highlighted diverse biological functions, including synapse function, neuronal differentiation, axon guidance and PD metabolism. Specifically, the authors suggest that the mmu_circRNA_0003292-miRNA-132-Nr4a2 pathway can be involved in the regulation of pathogenic mechanisms [205]. Using the same mouse model of PD, a recent report has shown a decreased expression of circDLGAP4 upon MPTP treatment and an analogous deregulation pattern in MPP+ treated cell models [206].…”