title: Up-regulation of neural and cell cycle-related microRNAs in brain of amyotrophic lateral sclerosis mice at late disease stage.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron degeneration in motor cortex, brainstem and spinal cord. microRNAs (miRNAs) are small non-coding RNAs that bind complementary target sequences and modulate gene expression; they are key molecules for establishing a neuronal phenotype, and in neurodegeneration. Here we investigated neural miR-9, miR-124a, miR-125b, miR-219, miR-134, and cell cycle-related miR-19a and -19b, in G93A-SOD1 mouse brain in pre-symptomatic and late stage disease.
  
  
  RESULTS
  Expression of miR-9, miR-124a, miR-19a and -19b was significantly increased in G93A-SOD1 whole brain at late stage disease compared to B6.SJL and Wt-SOD1 control brains. These miRNAs were then analyzed in manually dissected SVZ, hippocampus, primary motor cortex and brainstem motor nuclei in 18-week-old ALS mice compared to same age controls. In SVZ and hippocampus miR-124a was up-regulated, miR-219 was down-regulated, and numbers of neural stem progenitor cells (NSPCs) were significantly increased. In G93A-SOD1 brainstem motor nuclei and primary motor cortex, miR-9 and miR-124a were significantly up-regulated, miR-125b expression was also increased. miR-19a and -19b were up-regulated in primary motor cortex and hippocampus, respectively. Expression analysis of predicted miRNA targets identified miRNA/target gene pairs differentially expressed in G93A-SOD1 brain regions compared to controls.
  
  
  CONCLUSIONS
  Hierarchical clustering analysis, identifying two clusters of miRNA/target genes, one characterizing brainstem motor nuclei and primary motor cortex, the other hippocampus and SVZ, suggests that altered expression of neural and cell cycle-related miRNAs in these brain regions might contribute to ALS pathogenesis in G93A-SOD1 mice. Re-establishing their expression to normal levels could be a new therapeutic approach to ALS.
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. stefania.marcuzzo@istituto-besta.it.
authors: Stefania
authors: S
authors: Marcuzzo
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. silvia.bonanno@istituto-besta.it.
authors: Silvia
authors: S
authors: Bonanno
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. dimos.kapetis@istituto-besta.it.
authors: Dimos
authors: D
authors: Kapetis
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. claudia.barzago@istituto-besta.it.
authors: Claudia
authors: C
authors: Barzago
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. paola.cavalcante@istituto-besta.it.
authors: Paola
authors: P
authors: Cavalcante
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. sara.d'alessandro@instituto-besta.it.
authors: Sara
authors: S
authors: D'Alessandro
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. renato.mantegazza@istituto-besta.it.
authors: Renato
authors: R
authors: Mantegazza
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, Milan, 20133, Italy. pbernasconi@istituto-besta.it.
authors: Pia
authors: P
authors: Bernasconi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002452:Cell Count; D002453:Cell Cycle; D002454:Cell Differentiation; D018450:Disease Progression; D006624:Hippocampus / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D013482:Superoxide Dismutase
references: Ann Neurol. 2015 Jan;77(1):75-99
references: 25381879
references: Neurol Res. 2011 Jan;33(1):33-7
references: 20810028
references: Stem Cells. 2011 Jun;29(6):907-12
references: 21557389
references: Nat Neurosci. 2009 Apr;12(4):369-70
references: 19322237
references: Eur J Neurosci. 2004 Oct;20(7):1745-51
references: 15379995
references: Neuromolecular Med. 2009;11(3):141-52
references: 19598002
references: Exp Neurol. 2014 Mar;253:91-101
references: 24365539
references: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13111-6
references: 20616011
references: Hum Mol Genet. 2013 Oct 15;22(20):4127-35
references: 23740943
references: Front Cell Neurosci. 2014 Jan 30;8:15
references: 24523674
references: Curr Biol. 2002 Apr 30;12(9):735-9
references: 12007417
references: Neurosci Lett. 2011 Jul 15;499(1):9-13
references: 21616125
references: Stem Cells Dev. 2010 Jul;19(7):935-50
references: 20128659
references: J Neurosci. 2010 Nov 10;30(45):14931-6
references: 21068294
references: Science. 2009 Dec 11;326(5959):1549-54
references: 20007902
references: Nat Cell Biol. 2004 Jun;6(6):547-54
references: 15156153
references: Physiol Genomics. 2011 May 1;43(10):571-80
references: 21385946
references: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17016-21
references: 17942673
references: Nucleic Acids Res. 2013 Aug;41(15):e146
references: 23771142
references: Genome Res. 2011 May;21(5):798-810
references: 21451113
references: Nature. 2001 Mar 1;410(6824):37-40
references: 11242034
references: Neurosci Lett. 2010 May 26;476(1):18-22
references: 20347935
references: Nat Rev Mol Cell Biol. 2014 Aug;15(8):509-24
references: 25027649
references: J Comp Neurol. 2006 Jul 20;497(3):468-88
references: 16736475
references: Cytotechnology. 2003 Nov;43(1-3):19-25
references: 19003203
references: Eur J Neurosci. 2005 Mar;21(6):1469-77
references: 15845075
references: Front Cell Neurosci. 2013 Dec 19;7:265
references: 24391543
references: Nat Rev Genet. 2009 Aug;10(8):578-85
references: 19609263
references: Stem Cells Dev. 2007 Aug;16(4):579-88
references: 17784831
references: J Neurosci Res. 2005 Jul 15;81(2):163-71
references: 15948155
references: Bioinformatics. 2005 May 1;21(9):2067-75
references: 15657102
references: J Neurosci. 2011 Mar 2;31(9):3407-22
references: 21368052
references: Exp Neurol. 2011 Sep;231(1):30-7
references: 21620832
references: J Biotechnol. 1999 Oct 8;75(2-3):291-5
references: 10617337
references: Mol Neurobiol. 2015 Jun;51(3):1249-62
references: 24973986
references: Nat Rev Neurol. 2014 Nov;10(11):661-70
references: 25311585
references: Gene Ther. 2011 Dec;18(12):1121-6
references: 21633392
references: Nature. 1999 Aug 12;400(6745):687-93
references: 10458166
references: J Neurosci Res. 2002 Sep 15;69(6):745-9
references: 12205667
references: PLoS One. 2013;8(9):e74315
references: 24066135
references: Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13812-7
references: 20643953
references: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9023-7
references: 12853570
references: Cell Mol Life Sci. 2014 Aug;71(16):2975-95
references: 24519472
references: Stem Cells. 2006 Apr;24(4):857-64
references: 16357340
references: Nature. 2006 Jan 19;439(7074):283-9
references: 16421561
references: J Clin Pathol. 2013 Mar;66(3):249-52
references: 23172553
references: Annu Rev Biomed Eng. 2010 Aug 15;12:1-27
references: 20415587
references: Neuron. 2010 Mar 11;65(5):597-611
references: 20223197
references: Front Cell Neurosci. 2014 Jun 25;8:175
references: 25009466
references: Behav Brain Res. 2009 Jun 25;200(2):315-22
references: 19374018
references: Nat Neurosci. 2009 Apr;12(4):399-408
references: 19287386
references: J Neurol Sci. 1997 Oct;152 Suppl 1:S67-73
references: 9419057
references: EMBO J. 1997 Apr 15;16(8):1909-20
references: 9155017
references: Endocr Rev. 2001 Apr;22(2):153-83
references: 11294822
references: Exp Neurol. 2012 Jun;235(2):419-26
references: 22085592
references: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7
references: 14660786
references: J Biochem. 2010 Oct;148(4):381-92
references: 20833630
references: Neurol Res. 2007 Mar;29(2):204-9
references: 17439705
references: J Biomed Inform. 2011 Oct;44(5):839-47
references: 21605702