Circular RNA (circRNA) is a type of non-coding RNA that is widely expressed in mammals. It is highly conserved and abundantly expressed in the brain. Here, we report the regulatory role of circRNA derived from the pantothenate kinase 1 (Pank1) gene (circ-Pank1) in Parkinson’s disease (PD). Circ-Pank1 is highly expressed in the substantia nigra (SN) of PD model mice treated with rotenone and in the MN9D cell model of dopaminergic neurons. The circ-Pank1 knockdown ameliorated dopaminergic neuron damage and locomotor dysfunction after the treatment with rotenone. We found that circ-Pank1 could adsorb miR-7a-5p and upregulate the expression of α-synuclein (α-syn), which is a molecular hallmark closely related to PD. The inhibition of miR-7a-5p reversed the circ-Pank1 knockdown-induced amelioration of dopaminergic neuron injury. In conclusion, circ-Pank1 is overexpressed in PD and enhances the locomotor dysfunction via the miR-7a-5p/α-syn signaling axis. We revealed the functional role of circRNAs in the progression of PD and provided a potential target for noncoding RNAs in delaying the progression of PD.
Background/Aims: The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway plays a protective role in both acute neuronal damage and chronic neurodegeneration-related oxidative stress. Circular RNAs (circRNAs) are involved with various diseases in the central nervous system (CNS). This study aimed to identify the key circRNAs involved in Nrf2-neuroprotection against oxidative stress. Methods: The differentially expressed circRNAs (DEcircRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice were identified by microarray analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was then used to validate the expression of selected DEcircRNAs in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice. Based on our previous microarray analysis of the differentially expressed mRNAs (DEmRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice, the DEcircRNA-miRNA-DEmRNA interaction network was constructed. Functional annotation of DEmRNAs that shared the same binding miRNAs with DEcircRNAs was performed using gene ontology (GO) and pathway analyses. Results: A total of 65 and 150 significant DEcircRNAs were obtained in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, respectively, and seventeen shared DEcircRNAs were found in both these two tissues. The qRT-PCR results were generally consistent with the microarray results. The DEcircRNA-miRNA-DEmRNA interaction network and pathway analysis indicated that mmu_circRNA_34132, mmu_circRNA_017077 and mmu-circRNA-015216 might be involved with Nrf2-mediated neuroprotection against oxidative stress. Mmu_circRNA_015216 and mmu_circRNA_017077 might play roles in the Nrf2-related transcriptional misregulation and Nrf2-mediated processes of rheumatoid arthritis, respectively. In addition to these two processes, mmu_circRNA_34132 may be a potential regulator of Nrf2-mediated protection for diabetes mellitus and Nrf2-mediated defence against ROS in hearts. Conclusion: In conclusion, our study identified the key DEcircRNAs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, which might provide new clues for further exploring the mechanism of Nrf2-mediated neuroprotection against oxidative stress and other Nrf2-mediated processes.
Background Nrf2 (nuclear factor, erythroid 2 like 2) is believed to play a major role in neurodegenerative diseases. The present study attempts to investigate the hippocampal circRNA and lncRNA expression profiles associated with Nrf2-mediated neuroprotection. Methods The hippocampal mRNA, circRNA and lncRNA expression profiles of Nrf2 (−/−) mice were determined by a microarray analysis. Bioinformatics analyses, including identification of differentially expressed mRNAs (DEmRNAs), circRNAs (DEcircRNAs) and lncRNAs (DElncRNAs), DEcircRNA-miRNA-DEmRNA interaction network construction, DElncRNA-DEmRNA co-expression network construction, and biological function annotation, were conducted. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the dysregulated expression of circRNAs and lncRNAs derived from the microarray data of the hippocampus of Nrf2 (−/−) mice. Results Compared to wild-type Nrf2 (+/+) mice, 412 DEmRNAs (109 up- and 303 down-regulated mRNAs), 1279 DEcircRNAs (632 up- and 647 down-regulated circRNAs), and 303 DElncRNAs (50 up- and 253 down-regulated lncRNAs) were identified in the hippocampus of Nrf2 (−/−) mice. Additionally, in the qRT-PCR validation results, the expression patterns of selected DEcircRNAs and DElncRNAs were generally consistent with results in the microarray data. The DEcircRNA-miRNA-DEmRNA interaction networks revealed that mmu_circRNA_44531, mmu_circRNA_34132, mmu_circRNA_000903, mmu_circRNA_018676, mmu_circRNA_45901, mmu_circRNA_33836, mmu_circRNA_ 34137, mmu_circRNA_34106, mmu_circRNA_008691, and mmu_circRNA_003237 were predicted to compete with 47, 54, 45, 57, 63, 81, 121, 85, 181, and 43 DEmRNAs, respectively. ENSMUST00000125413, NR_028123, uc008nfy.1, AK076764, AK142725, AK080547, and AK035903 were co-expressed with 178, 89, 149, 179, 142, 55, and 112 DEmRNAs in the Nrf2 (−/−) hippocampus, respectively. Conclusion Our study might contribute to exploring the key circRNAs and lncRNAs associated with Nrf2-mediated neuroprotection.
The importance of epitranscriptomics in regulating gene expression has received widespread attention. Recently, RNA methylation modifications, particularly N6-methyladenosine (m6A), have received marked attention. m6A, the most common and abundant type of eukaryotic methylation modification in RNAs, is a dynamic reversible modification that regulates nuclear splicing, stability, translation, and subcellular localization of RNAs. These processes are involved in the occurrence and development of many diseases. An increasing number of studies have focused on the role of m6A modification in Alzheimer’s disease, which is the most common neurodegenerative disease. This review focuses on the general features, mechanisms, and functions of m6A methylation modification and its role in Alzheimer’s disease.
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