Downregulated miR-18b-5p triggers apoptosis by inhibition of calcium signaling and neuronal cell differentiation in transgenic SOD1 (G93A) mice and SOD1 (G17S and G86S) ALS patients
| Autor: | Je Young Shin, Kyung Won Choi, Ki Yoon Kim, Yoon-Ho Hong, Somyung Lee, Jin Young Kim, Jung-Joon Sung, Wooseok Im, Yu Ri Kim, Manho Kim, Mijung Lee, Jong Il Kim |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cognitive Neuroscience Cellular differentiation Transgene Induced Pluripotent Stem Cells Down-Regulation Apoptosis Mice Transgenic Hif1α Biology medicine.disease_cause lcsh:RC346-429 Cell Line Mice 03 medical and health sciences Cellular and Molecular Neuroscience Superoxide Dismutase-1 0302 clinical medicine Downregulation and upregulation microRNA Gene expression medicine Animals Humans Mctp1 and Rarb MEF2C Calcium Signaling Transcription factor lcsh:Neurology. Diseases of the nervous system Neurons Mutation Superoxide Dismutase Research Amyotrophic Lateral Sclerosis Cell Differentiation Mef2c Cell biology MicroRNAs 030104 developmental biology miRNAs Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Translational Neurodegeneration, Vol 9, Iss 1, Pp 1-21 (2020) Translational Neurodegeneration |
| ISSN: | 2047-9158 |
| DOI: | 10.1186/s40035-020-00203-4 |
| Popis: | 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 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 Hif1α 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 Hif1α 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 induces intracellular Ca2+ levels and reduces cell differentiation, respectively. We confirmed that miR-18b-5p pathway was also observed in G93A Tg, 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 Hif1α, 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. |
| Databáze: | OpenAIRE |
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