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.
Amyotrophic Lateral Sclerosis
/ genetics
Animals
Apoptosis
/ physiology
Calcium Signaling
/ physiology
Cell Differentiation
/ physiology
Cell Line
Down-Regulation
/ physiology
Humans
Induced Pluripotent Stem Cells
/ metabolism
Mice
Mice, Transgenic
MicroRNAs
/ antagonists & inhibitors
Neurons
/ metabolism
Superoxide Dismutase
/ genetics
Superoxide Dismutase-1
/ genetics
Hif1α
Mctp1 and Rarb
Mef2c
miRNAs
Journal
Translational neurodegeneration
ISSN: 2047-9158
Titre abrégé: Transl Neurodegener
Pays: England
ID NLM: 101591861
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
22
05
2019
accepted:
01
06
2020
entrez:
2
7
2020
pubmed:
2
7
2020
medline:
20
7
2021
Statut:
epublish
Résumé
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. 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. 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 Ca 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.
Sections du résumé
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 Ca
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.
Identifiants
pubmed: 32605607
doi: 10.1186/s40035-020-00203-4
pii: 10.1186/s40035-020-00203-4
pmc: PMC7328278
doi:
Substances chimiques
MIRN18 microRNA, human
0
MicroRNAs
0
SOD1 protein, human
0
SOD1 G93A protein
EC 1.15.1.1
Superoxide Dismutase
EC 1.15.1.1
Superoxide Dismutase-1
EC 1.15.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Références
Neurosci Lett. 2017 Jan 1;636:32-39
pubmed: 27507699
Nat Protoc. 2008;3(12):1888-94
pubmed: 19008875
Cell. 2009 Mar 20;136(6):1001-4
pubmed: 19303844
Oncogene. 2010 Jul 29;29(30):4362-8
pubmed: 20498629
Neuron. 2011 Oct 20;72(2):245-56
pubmed: 21944778
Brain. 2010 Feb;133(Pt 2):465-81
pubmed: 20032086
EMBO J. 2015 Nov 3;34(21):2601-3
pubmed: 26369718
Nat Rev Mol Cell Biol. 2014 Aug;15(8):509-24
pubmed: 25027649
Exp Neurol. 1999 Nov;160(1):28-39
pubmed: 10630188
Nature. 2016 Nov 10;539(7628):197-206
pubmed: 27830784
Hum Mol Genet. 2013 Feb 1;22(3):608-20
pubmed: 23125283
Cell Death Differ. 2014 Jan;21(1):136-45
pubmed: 24185621
Circ Res. 2008 Nov 7;103(10):1139-46
pubmed: 18849322
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8721-6
pubmed: 16731620
Biochem Biophys Res Commun. 2015 Aug 14;464(1):236-43
pubmed: 26102026
J Neurosci. 2008 Dec 31;28(53):14341-6
pubmed: 19118166
EMBO J. 2017 Oct 16;36(20):2931-2950
pubmed: 28916614
Front Cell Neurosci. 2013 Dec 03;7:239
pubmed: 24348333
Cell Stem Cell. 2014 Jun 5;14(6):796-809
pubmed: 24704493
Cells. 2014 Sep 11;3(3):899-913
pubmed: 25216032
Genes (Basel). 2017 Nov 27;8(12):
pubmed: 29186897
Neuron. 2013 Aug 7;79(3):416-38
pubmed: 23931993
Cell. 1995 Dec 15;83(6):835-9
pubmed: 8521507
Int J Cancer. 1998 Jan 5;75(1):88-95
pubmed: 9426695
J Biol Chem. 2005 Jan 14;280(2):1641-51
pubmed: 15528213
Hum Mol Genet. 2013 Oct 15;22(20):4127-35
pubmed: 23740943
Nature. 1993 Mar 4;362(6415):59-62
pubmed: 8446170
Science. 1992 Mar 27;255(5052):1707-10
pubmed: 1553558
Oncogene. 2003 Aug 21;22(35):5515-8
pubmed: 12934111
Nature. 1998 Oct 15;395(6703):645-8
pubmed: 9790183
Nat Rev Neurol. 2015 May;11(5):266-79
pubmed: 25896087
Gene. 2007 Jan 15;386(1-2):73-80
pubmed: 17045424
Nat Rev Neurosci. 2006 Dec;7(12):911-20
pubmed: 17115073
Science. 2009 Feb 27;323(5918):1205-8
pubmed: 19251627
Cell. 2007 Dec 14;131(6):1097-108
pubmed: 18083100
Mol Cell. 2007 Aug 3;27(3):435-48
pubmed: 17679093
Neuropathology. 2005 Dec;25(4):381-7
pubmed: 16382789
Nature. 2010 Jul 29;466(7306):637-41
pubmed: 20671708
Lancet Neurol. 2010 Oct;9(10):995-1007
pubmed: 20864052
Exp Mol Med. 2016 Dec 9;48(12):e276
pubmed: 27932790
J Clin Invest. 2015 May;125(5):1767-79
pubmed: 25932674
Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20
pubmed: 18434550
Nat Rev Neurosci. 2006 Sep;7(9):710-23
pubmed: 16924260
EMBO J. 2001 Jun 1;20(11):2690-701
pubmed: 11387204
Nature. 2003 Sep 25;425(6956):415-9
pubmed: 14508493
Neurobiol Dis. 2013 Jan;49:107-17
pubmed: 22975021
J Clin Invest. 2012 Sep;122(9):3063-87
pubmed: 22863620
FEBS Lett. 2008 Aug 20;582(19):2899-904
pubmed: 18656473
Nucleic Acids Res. 2010 Nov;38(20):7219-35
pubmed: 20591823
Cell. 2009 Jan 9;136(1):75-84
pubmed: 19135890
Sci Rep. 2015 Nov 20;5:16887
pubmed: 26586297
Hum Mol Genet. 2012 Jul 1;21(13):2899-911
pubmed: 22454397
Neurobiol Dis. 2011 Jun;42(3):265-75
pubmed: 21296666
Acta Neuropathol. 2011 Feb;121(2):193-205
pubmed: 20936480
J Neurochem. 2015 Nov;135(3):492-507
pubmed: 26195140