Background:MicroRNAs(miRNAs)are endogenous non-coding RNAS that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases.Overexpressed miRNAs play an important ro...Background:MicroRNAs(miRNAs)are endogenous non-coding RNAS that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases.Overexpressed miRNAs play an important role in amyotrophic lateral sclerosis(ALS);however,the pathogenic mechanisms of deregulated miRNAS are still unclear.Methods:We aimed to assess the dysfunction of RNAS or miRNAs in fALS(SOD1 mutations).We compared the RNA-seq of subcellular fractions in NSC-34 WT(hSOD1)and MT(hSOD1(G93A))cells to find altered RNAs or miRNAs.We identified that Hif1a and Mef2c were upregulated,and Mctp1 and Rarb were downregulated in the cytoplasm of NSC-34 MT cells.Results:SOD1 mutations decreased the level of miR-18b-5p.Induced Hif1a which is the target for miR-18b increased Mef2c expression as a transcription factor.Mef2c upregulated miR-206 as a transcription factor.Inhibition of Mctp1 and Rarb,which are targets of miR-206,induced intracellular Ca^2+ levels and reduced cell differentiation,respectively.The miR-18b-5p pathway was also observed in G93A Tg mice,fALS(G86S)patient,and iPSC-derived motor neurons from fALS(G17S)patient.Conclusions:Our data indicate that SOD1 mutation decreases miR-18b-5p,which sequentially regulates Hif1a,Mef2c,miR-206,Mctp1 and Rarb in fALS-linked SOD1 mutation.These results provide new insights into the downregulation of miR-18b-5p-dependent pathogenic mechanisms of ALS.展开更多
基金This research was supported by the Brain Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT(2017M3C7A102536521 and 2018R1A5A202596413).
文摘Background:MicroRNAs(miRNAs)are endogenous non-coding RNAS that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases.Overexpressed miRNAs play an important role in amyotrophic lateral sclerosis(ALS);however,the pathogenic mechanisms of deregulated miRNAS are still unclear.Methods:We aimed to assess the dysfunction of RNAS or miRNAs in fALS(SOD1 mutations).We compared the RNA-seq of subcellular fractions in NSC-34 WT(hSOD1)and MT(hSOD1(G93A))cells to find altered RNAs or miRNAs.We identified that Hif1a and Mef2c were upregulated,and Mctp1 and Rarb were downregulated in the cytoplasm of NSC-34 MT cells.Results:SOD1 mutations decreased the level of miR-18b-5p.Induced Hif1a which is the target for miR-18b increased Mef2c expression as a transcription factor.Mef2c upregulated miR-206 as a transcription factor.Inhibition of Mctp1 and Rarb,which are targets of miR-206,induced intracellular Ca^2+ levels and reduced cell differentiation,respectively.The miR-18b-5p pathway was also observed in G93A Tg mice,fALS(G86S)patient,and iPSC-derived motor neurons from fALS(G17S)patient.Conclusions:Our data indicate that SOD1 mutation decreases miR-18b-5p,which sequentially regulates Hif1a,Mef2c,miR-206,Mctp1 and Rarb in fALS-linked SOD1 mutation.These results provide new insights into the downregulation of miR-18b-5p-dependent pathogenic mechanisms of ALS.
