title: The multifaceted role of glial cells in amyotrophic lateral sclerosis.
abstract: Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia-neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.
authors.affiliation: Department of Neuropathology, German Center for Neurodegenerative Diseases (DZNE), Paul-Ehrlich-Strasse 17, 72076, Tübingen, Germany.
authors.forename: Chiara F
authors.initials: CF
authors.lastname: Valori
authors.forename: Liliana
authors.initials: L
authors.lastname: Brambilla
authors.forename: Francesca
authors.initials: F
authors.lastname: Martorana
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D026901:Membrane Transport Proteins; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D035582:Transcription Factor TFIIIA / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D035582:Transcription Factor TFIIIA; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
references.citation: Science. 2013 Jan 11;339(6116):156-61
references.pmid: 23307732
references.citation: J Neurosci. 2000 Jan 15;20(2):660-5
references.pmid: 10632595
references.citation: J Neurosci. 2000 Sep 1;20(17):6404-12
references.pmid: 10964946
references.citation: J Cell Biol. 2005 Apr 25;169(2):285-95
references.pmid: 15837803
references.citation: J Neurosci. 2008 Apr 16;28(16):4115-22
references.pmid: 18417691
references.citation: N Engl J Med. 1992 May 28;326(22):1464-8
references.pmid: 1349424
references.citation: Acta Neuropathol. 2008 Jan;115(1):115-22
references.pmid: 17786458
references.citation: Neuron. 2011 Oct 20;72(2):257-68
references.pmid: 21944779
references.citation: Nature. 2011 Aug 21;477(7363):211-5
references.pmid: 21857683
references.citation: Acta Neuropathol. 2008 Aug;116(2):169-82
references.pmid: 18481073
references.citation: PLoS One. 2012;7(4):e34776
references.pmid: 22509356
references.citation: J Biol Chem. 2005 Oct 14;280(41):34840-8
references.pmid: 16091361
references.citation: J Neurol Neurosurg Psychiatry. 2011 Nov;82(11):1239-43
references.pmid: 21613650
references.citation: Exp Neurol. 2008 Jun;211(2):423-32
references.pmid: 18410928
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):E756-65
references.pmid: 23388633
references.citation: Science. 2009 Feb 27;323(5918):1208-1211
references.pmid: 19251628
references.citation: Arch Neurol. 2010 Apr;67(4):455-61
references.pmid: 20385912
references.citation: Cell Stem Cell. 2008 Dec 4;3(6):649-57
references.pmid: 19041781
references.citation: Glia. 2009 Aug 1;57(10):1130-42
references.pmid: 19115383
references.citation: Neurobiol Aging. 2011 Mar;32(3):553.e27-30
references.pmid: 20561714
references.citation: Nat Biotechnol. 2011 Aug 10;29(9):824-8
references.pmid: 21832997
references.citation: Neurobiol Aging. 2012 Jan;33(1):208.e1-5
references.pmid: 21852022
references.citation: Cell Death Differ. 2009 Mar;16(3):378-85
references.pmid: 19057621
references.citation: J Neural Transm Suppl. 1993;39:223-33
references.pmid: 8360662
references.citation: Nat Genet. 2008 May;40(5):572-4
references.pmid: 18372902
references.citation: Brain Behav Immun. 2011 Jul;25(5):1025-35
references.pmid: 21176785
references.citation: Acta Neuropathol. 2011 May;121(5):623-34
references.pmid: 21287393
references.citation: Nature. 2012 Aug 23;488(7412):499-503
references.pmid: 22801503
references.citation: Mol Cell. 2012 Feb 24;45(4):553-66
references.pmid: 22365832
references.citation: Nature. 1993 Mar 4;362(6415):59-62
references.pmid: 8446170
references.citation: Cell Death Differ. 2013 Jan;20(1):21-30
references.pmid: 22722335
references.citation: EMBO J. 2013 Jul 3;32(13):1917-26
references.pmid: 23714777
references.citation: Curr Biol. 2000 Dec 14-28;10(24):1603-6
references.pmid: 11137014
references.citation: Acta Neuropathol. 2011 Apr;121(4):555-7
references.pmid: 21327942
references.citation: Glia. 1998 Jul;23(3):249-56
references.pmid: 9633809
references.citation: Ann Neurol. 1995 Jul;38(1):73-84
references.pmid: 7611729
references.citation: Curr Biol. 2007 Aug 21;17(16):1438-43
references.pmid: 17702576
references.citation: J Neurosci. 2008 Dec 10;28(50):13574-81
references.pmid: 19074031
references.citation: EMBO J. 2007 Sep 19;26(18):4149-59
references.pmid: 17762863
references.citation: Nat Neurosci. 2007 May;10(5):608-14
references.pmid: 17435754
references.citation: Neuron. 2010 Nov 18;68(4):668-81
references.pmid: 21092857
references.citation: Science. 2008 Mar 21;319(5870):1668-72
references.pmid: 18309045
references.citation: Hum Mol Genet. 2003 Oct 1;12(19):2519-32
references.pmid: 12915461
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4465-70
references.pmid: 19251638
references.citation: Neuron. 2011 Oct 20;72(2):245-56
references.pmid: 21944778
references.citation: Arch Neurol. 1993 Jan;50(1):30-6
references.pmid: 8093428
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13901-6
references.pmid: 11095709
references.citation: Science. 2009 Feb 27;323(5918):1205-8
references.pmid: 19251627
references.citation: Hum Mol Genet. 2011 Jan 15;20(2):286-93
references.pmid: 20962037
references.citation: ASN Neuro. 2011 Dec 19;3(5):271-9
references.pmid: 22103264
references.citation: J Neurol Sci. 2010 Sep 15;296(1-2):59-63
references.pmid: 20621307
references.citation: Neurobiol Aging. 2012 May;33(5):1016.e1-7
references.pmid: 21802176
references.citation: Science. 2003 Oct 3;302(5642):113-7
references.pmid: 14526083
references.citation: Nat Neurosci. 2006 Mar;9(3):408-19
references.pmid: 16474388
references.citation: Am J Pathol. 1992 Mar;140(3):691-707
references.pmid: 1347673
references.citation: J Neuropathol Exp Neurol. 2007 Mar;66(3):177-83
references.pmid: 17356379
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15558-63
references.pmid: 18809917
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14825-30
references.pmid: 17804792
references.citation: J Cell Sci. 2013 Jan 15;126(Pt 2):580-92
references.pmid: 23178947
references.citation: EMBO Mol Med. 2013 Jan;5(1):64-79
references.pmid: 23143995
references.citation: Cell Death Differ. 2011 May;18(5):754-68
references.pmid: 21072055
references.citation: Genes Dev. 2012 May 1;26(9):891-907
references.pmid: 22549954
references.citation: Trends Immunol. 2010 Jan;31(1):7-17
references.pmid: 19879804
references.citation: Neurosci Lett. 2006 Sep 1;404(3):315-9
references.pmid: 16806703
references.citation: Acta Neuropathol. 2009 Oct;118(4):561-73
references.pmid: 19449021
references.citation: Science. 2006 Jun 2;312(5778):1389-92
references.pmid: 16741123
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16021-6
references.pmid: 17043238
references.citation: EMBO J. 2010 Aug 18;29(16):2841-57
references.pmid: 20606625
references.citation: Methods Mol Biol. 2012;814:23-45
references.pmid: 22144298
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17803-8
references.pmid: 21969586
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17913-8
references.pmid: 18997009
references.citation: J Anat. 2012 Sep;221(3):252-62
references.pmid: 22738374
references.citation: Cell Stem Cell. 2008 Dec 4;3(6):637-48
references.pmid: 19041780
references.citation: Nat Rev Neurol. 2011 Oct 11;7(11):639-49
references.pmid: 21989247
references.citation: Brain. 2011 Sep;134(Pt 9):2627-41
references.pmid: 21908873
references.citation: Exp Neurol. 2006 Sep;201(1):120-30
references.pmid: 16753145
references.citation: Nat Rev Neurol. 2011 Nov;7(11):616-30
references.pmid: 22051914
references.citation: Nat Neurosci. 2007 May;10(5):615-22
references.pmid: 17435755
references.citation: Nucleic Acids Res. 2000 May 1;28(9):1986-93
references.pmid: 10756201
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):627-32
references.pmid: 22203986
references.citation: Glia. 2013 Mar;61(3):409-19
references.pmid: 23281114
references.citation: J Neurol Sci. 2000 Aug 15;177(2):114-23
references.pmid: 10980307
references.citation: Nat Neurosci. 2006 Jan;9(1):108-18
references.pmid: 16369483
references.citation: Acta Neuropathol. 2011 Feb;121(2):207-18
references.pmid: 21052700
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1604-9
references.pmid: 11818550
references.citation: Mol Biol Cell. 2009 Mar;20(5):1478-92
references.pmid: 19144827
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18126-31
references.pmid: 22010221
references.citation: Nature. 2012 Jul 26;487(7408):443-8
references.pmid: 22801498
references.citation: J Exp Med. 2011 Nov 21;208(12):2429-47
references.pmid: 22084410
references.citation: Hum Mol Genet. 2013 Oct 1;22(19):3883-93
references.pmid: 23727833
references.citation: Hum Mol Genet. 2012 Feb 15;21(4):826-40
references.pmid: 22072391
references.citation: Nat Neurosci. 2013 May;16(5):571-9
references.pmid: 23542689
references.citation: Cell Death Differ. 2008 Nov;15(11):1691-700
references.pmid: 18617894
references.citation: Glia. 2010 May;58(7):831-8
references.pmid: 20140958
references.citation: J Clin Invest. 2012 Sep;122(9):3063-87
references.pmid: 22863620
references.citation: Nature. 2010 May 13;465(7295):223-6
references.pmid: 20428114
references.citation: Clin Neuropathol. 2012 Nov-Dec;31(6):418-23
references.pmid: 22762947
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4697-702
references.pmid: 23401527
references.citation: Nature. 2009 Feb 5;457(7230):675-7
references.pmid: 19194443
references.citation: Expert Rev Neurother. 2009 Jul;9(7):1059-71
references.pmid: 19589054
references.citation: J Neurosci. 2008 Oct 8;28(41):10234-44
references.pmid: 18842883
references.citation: Nat Genet. 2001 Oct;29(2):160-5
references.pmid: 11586297
references.citation: Nat Neurosci. 2008 Nov;11(11):1294-301
references.pmid: 18931666
references.citation: Clin Neuropathol. 1989 Nov-Dec;8(6):289-94
references.pmid: 2533530
references.citation: CNS Drugs. 2011 Aug;25(8):641-58
references.pmid: 21790208
references.citation: Science. 2006 Oct 6;314(5796):130-3
references.pmid: 17023659
references.citation: Brain. 2013 Feb;136(Pt 2):471-82
references.pmid: 23378219
references.citation: J Neurochem. 2012 Apr;121(1):4-27
references.pmid: 22251135
references.citation: Nat Neurosci. 2008 Mar;11(3):251-3
references.pmid: 18246065
references.citation: Hum Mol Genet. 2010 Mar 1;19(5):815-24
references.pmid: 20008901
references.citation: Neuron. 1997 Feb;18(2):327-38
references.pmid: 9052802
references.citation: CNS Neurol Disord Drug Targets. 2007 Jun;6(3):219-33
references.pmid: 17511618
references.citation: J Neurosci. 2011 Jan 12;31(2):538-48
references.pmid: 21228163
references.citation: Glia. 2008 Jan 15;56(2):200-8
references.pmid: 18023016