Cellular and Molecular Life Sciences

, Volume 71, Issue 2, pp 287–297 | Cite as

The multifaceted role of glial cells in amyotrophic lateral sclerosis

  • Chiara F. Valori
  • Liliana Brambilla
  • Francesca Martorana
  • Daniela Rossi


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.


Amyotrophic lateral sclerosis Glia Astrocytes Microglia Neurodegeneration Transgenic animals 



Chiara F. Valori receives a stipend from the Swiss National Science Foundation (Grant 31003A-132864). Daniela Rossi received funds from the Telethon Foundation (Grant GGP05244) to study the role of glial cells in ALS pathogenesis and progression. Figures were produced using Servier Medical Art (


  1. 1.
    Hardiman O, van den Berg LH, Kiernan MC (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol 7(11):639–649. doi: 10.1038/nrneurol.2011.153 PubMedGoogle Scholar
  2. 2.
    Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18(2):327–338PubMedGoogle Scholar
  3. 3.
    Mendonca DM, Chimelli L, Martinez AM (2006) Expression of ubiquitin and proteasome in motorneurons and astrocytes of spinal cords from patients with amyotrophic lateral sclerosis. Neurosci Lett 404(3):315–319. doi: 10.1016/j.neulet.2006.06.009 PubMedGoogle Scholar
  4. 4.
    Pasinelli P, Houseweart MK, Brown RH Jr, Cleveland DW (2000) Caspase-1 and -3 are sequentially activated in motor neuron death in Cu, Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 97(25):13901–13906. doi: 10.1073/pnas.240305897 PubMedGoogle Scholar
  5. 5.
    Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62. doi: 10.1038/362059a0 PubMedGoogle Scholar
  6. 6.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319(5870):1668–1672. doi: 10.1126/science.1154584 PubMedGoogle Scholar
  7. 7.
    Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40(5):572–574. doi: 10.1038/ng.132 PubMedGoogle Scholar
  8. 8.
    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323(5918):1205–1208. doi: 10.1126/science.1166066 PubMedGoogle Scholar
  9. 9.
    Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211. doi: 10.1126/science.1165942 PubMedGoogle Scholar
  10. 10.
    Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T (2001) The gene encoding alsin, a protein with three guanine–nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29(2):160–165. doi: 10.1038/ng1001-160 PubMedGoogle Scholar
  11. 11.
    Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465(7295):223–226. doi: 10.1038/nature08971 PubMedGoogle Scholar
  12. 12.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256. doi: 10.1016/j.neuron.2011.09.011 PubMedCentralPubMedGoogle Scholar
  13. 13.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268. doi: 10.1016/j.neuron.2011.09.010 PubMedCentralPubMedGoogle Scholar
  14. 14.
    Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477(7363):211–215. doi: 10.1038/nature10353 PubMedCentralPubMedGoogle Scholar
  15. 15.
    Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488(7412):499–503. doi: 10.1038/nature11280 PubMedCentralPubMedGoogle Scholar
  16. 16.
    Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ (2011) Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol 7(11):616–630. doi: 10.1038/nrneurol.2011.152 PubMedGoogle Scholar
  17. 17.
    Allen NJ, Barres BA (2009) Neuroscience: glia––more than just brain glue. Nature 457(7230):675–677. doi: 10.1038/457675a PubMedGoogle Scholar
  18. 18.
    Stieber A, Gonatas JO, Gonatas NK (2000) Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuronal and astrocytic perikarya of mice expressing the SOD1 (G93A) mutation of familial amyotrophic lateral sclerosis. J Neurol Sci 177(2):114–123PubMedGoogle Scholar
  19. 19.
    Forsberg K, Andersen PM, Marklund SL, Brannstrom T (2011) Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis. Acta Neuropathol 121(5):623–634. doi: 10.1007/s00401-011-0805-3 PubMedCentralPubMedGoogle Scholar
  20. 20.
    Rossi D, Martorana F, Brambilla L (2011) Implications of gliotransmission for the pharmacotherapy of CNS disorders. CNS drugs 25(8):641–658. doi: 10.2165/11593090-000000000-00000 PubMedGoogle Scholar
  21. 21.
    Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho) physiology. J Neurochem 121(1):4–27. doi: 10.1111/j.1471-4159.2012.07664.x PubMedCentralPubMedGoogle Scholar
  22. 22.
    Gong YH, Parsadanian AS, Andreeva A, Snider WD, Elliott JL (2000) Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci: Off J Soc Neurosci 20(2):660–665Google Scholar
  23. 23.
    Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642):113–117. doi: 10.1126/science.1086071 PubMedGoogle Scholar
  24. 24.
    Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11(3):251–253. doi: 10.1038/nn2047 PubMedCentralPubMedGoogle Scholar
  25. 25.
    Wang L, Gutmann DH, Roos RP (2011) Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum Mol Genet 20(2):286–293. doi: 10.1093/hmg/ddq463 PubMedGoogle Scholar
  26. 26.
    Papadeas ST, Kraig SE, O'Banion C, Lepore AC, Maragakis NJ (2011) Astrocytes carrying the superoxide 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc Natl Acad Sci USA 108(43):17803–17808. doi: 10.1073/pnas.1103141108 Google Scholar
  27. 27.
    Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ (2008) Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 11(11):1294–1301. doi: 10.1038/nn.2210 PubMedCentralPubMedGoogle Scholar
  28. 28.
    Diaz-Amarilla P, Olivera-Bravo S, Trias E, Cragnolini A, Martinez-Palma L, Cassina P, Beckman J, Barbeito L (2011) Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 108(44):18126–18131. doi: 10.1073/pnas.1110689108 PubMedGoogle Scholar
  29. 29.
    Lepore AC, Dejea C, Carmen J, Rauck B, Kerr DA, Sofroniew MV, Maragakis NJ (2008) Selective ablation of proliferating astrocytes does not affect disease outcome in either acute or chronic models of motor neuron degeneration. Exp Neurol 211(2):423–432. doi: 10.1016/j.expneurol.2008.02.020 Google Scholar
  30. 30.
    Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC (2008) Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3(6):637–648. doi: 10.1016/j.stem.2008.09.017 PubMedGoogle Scholar
  31. 31.
    Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10(5):608–614. doi: 10.1038/nn1885 PubMedCentralPubMedGoogle Scholar
  32. 32.
    Ferraiuolo L, Higginbottom A, Heath PR, Barber S, Greenald D, Kirby J, Shaw PJ (2011) Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain: J Neurol 134(Pt 9):2627–2641. doi: 10.1093/brain/awr193 Google Scholar
  33. 33.
    Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK (2011) Astrocytes from familial to sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29(9):824–828. doi: 10.1038/nbt.1957 PubMedCentralPubMedGoogle Scholar
  34. 34.
    Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3(6):649–657. doi: 10.1016/j.stem.2008.10.001 PubMedGoogle Scholar
  35. 35.
    Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622. doi: 10.1038/nn1876 PubMedCentralPubMedGoogle Scholar
  36. 36.
    Phatnani HP, Guarnieri P, Friedman BA, Carrasco MA, Muratet M, O’Keeffe S, Nwakeze C, Pauli-Behn F, Newberry KM, Meadows SK, Tapia JC, Myers RM, Maniatis T (2013) Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci USA 110(8):E756–E765. doi: 10.1073/pnas.1222361110 PubMedGoogle Scholar
  37. 37.
    Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. New Eng J Med 326(22):1464–1468. doi: 10.1056/NEJM199205283262204 PubMedGoogle Scholar
  38. 38.
    Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38(1):73–84. doi: 10.1002/ana.410380114 PubMedGoogle Scholar
  39. 39.
    Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99(3):1604–1609. doi: 10.1073/pnas.032539299 PubMedGoogle Scholar
  40. 40.
    Guo H, Lai L, Butchbach ME, Stockinger MP, Shan X, Bishop GA, Lin CL (2003) Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 12(19):2519–2532. doi: 10.1093/hmg/ddg267 PubMedGoogle Scholar
  41. 41.
    Pardo AC, Wong V, Benson LM, Dykes M, Tanaka K, Rothstein JD, Maragakis NJ (2006) Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1 (G93A) mice. Exp Neurol 201(1):120–130. doi: 10.1016/j.expneurol.2006.03.028 PubMedGoogle Scholar
  42. 42.
    Sasabe J, Chiba T, Yamada M, Okamoto K, Nishimoto I, Matsuoka M, Aiso S (2007) d-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26(18):4149–4159. doi: 10.1038/sj.emboj.7601840 PubMedGoogle Scholar
  43. 43.
    Sasabe J, Miyoshi Y, Suzuki M, Mita M, Konno R, Matsuoka M, Hamase K, Aiso S (2012) d-amino acid oxidase controls motoneuron degeneration through d-serine. Proc Natl Acad Sci USA 109(2):627–632. doi: 10.1073/pnas.1114639109 PubMedGoogle Scholar
  44. 44.
    Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP, Beckman JS, Barbeito L, Radi R (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci: Off J Soc Neurosci 28(16):4115–4122. doi: 10.1523/JNEUROSCI.5308-07.2008 Google Scholar
  45. 45.
    Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci: Off J Soc Neurosci 28(50):13574–13581. doi: 10.1523/JNEUROSCI.4099-08.2008 Google Scholar
  46. 46.
    Miquel E, Cassina A, Martinez-Palma L, Bolatto C, Trias E, Gandelman M, Radi R, Barbeito L, Cassina P (2012) Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis. PLoS One 7(4):e34776. doi: 10.1371/journal.pone.0034776 PubMedCentralPubMedGoogle Scholar
  47. 47.
    Aebischer J, Cassina P, Otsmane B, Moumen A, Seilhean D, Meininger V, Barbeito L, Pettmann B, Raoul C (2011) IFNgamma triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1. Cell Death Differ 18(5):754–768. doi: 10.1038/cdd.2010.143 PubMedGoogle Scholar
  48. 48.
    Van Damme P, Bogaert E, Dewil M, Hersmus N, Kiraly D, Scheveneels W, Bockx I, Braeken D, Verpoorten N, Verhoeven K, Timmerman V, Herijgers P, Callewaert G, Carmeliet P, Van Den Bosch L, Robberecht W (2007) Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci USA 104(37):14825–14830. doi: 10.1073/pnas.0705046104 PubMedGoogle Scholar
  49. 49.
    Rossi D, Brambilla L, Valori CF, Roncoroni C, Crugnola A, Yokota T, Bredesen DE, Volterra A (2008) Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ 15(11):1691–1700. doi: 10.1038/cdd.2008.99 PubMedGoogle Scholar
  50. 50.
    Martorana F, Brambilla L, Valori CF, Bergamaschi C, Roncoroni C, Aronica E, Volterra A, Bezzi P, Rossi D (2012) The BH4 domain of Bcl-X (L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals. Hum Mol Genet 21(4):826–840. doi: 10.1093/hmg/ddr513 PubMedGoogle Scholar
  51. 51.
    Pun S, Santos AF, Saxena S, Xu L, Caroni P (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9(3):408–419. doi: 10.1038/nn1653 PubMedGoogle Scholar
  52. 52.
    Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, Barres BA, Rowitch DH (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26(9):891–907. doi: 10.1101/gad.188326.112 PubMedGoogle Scholar
  53. 53.
    Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Meth Mol Biol 814:23–45. doi: 10.1007/978-1-61779-452-0_3 Google Scholar
  54. 54.
    Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339(6116):156–161. doi: 10.1126/science.1227901 PubMedGoogle Scholar
  55. 55.
    Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23(3):249–256PubMedGoogle Scholar
  56. 56.
    Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9(1):108–118. doi: 10.1038/nn1603 PubMedGoogle Scholar
  57. 57.
    Roberts K, Zeineddine R, Corcoran L, Li W, Campbell IL, Yerbury JJ (2013) Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype. Glia 61(3):409–419. doi: 10.1002/glia.22444 PubMedGoogle Scholar
  58. 58.
    Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392. doi: 10.1126/science.1123511 PubMedGoogle Scholar
  59. 59.
    Gowing G, Philips T, Van Wijmeersch B, Audet JN, Dewil M, Van Den Bosch L, Billiau AD, Robberecht W, Julien JP (2008) Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase. J Neurosci: Off J Soc Neurosci 28(41):10234–10244. doi: 10.1523/JNEUROSCI.3494-08.2008 Google Scholar
  60. 60.
    Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 103(43):16021–16026. doi: 10.1073/pnas.0607423103 PubMedGoogle Scholar
  61. 61.
    Appel SH, Beers DR, Henkel JS (2010) T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 31(1):7–17. doi: 10.1016/ PubMedGoogle Scholar
  62. 62.
    Troost D, van den Oord JJ, de Jong JM, Swaab DF (1989) Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropathol 8(6):289–294PubMedGoogle Scholar
  63. 63.
    Kawamata T, Akiyama H, Yamada T, McGeer PL (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Amer J Pathol 140(3):691–707Google Scholar
  64. 64.
    Engelhardt JI, Tajti J, Appel SH (1993) Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol 50(1):30–36PubMedGoogle Scholar
  65. 65.
    Beers DR, Henkel JS, Zhao W, Wang J, Appel SH (2008) CD4 + T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci USA 105(40):15558–15563. doi: 10.1073/pnas.0807419105 PubMedGoogle Scholar
  66. 66.
    Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci USA 105(46):17913–17918. doi: 10.1073/pnas.0804610105 PubMedGoogle Scholar
  67. 67.
    Beers DR, Zhao W, Liao B, Kano O, Wang J, Huang A, Appel SH, Henkel JS (2011) Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun 25(5):1025–1035. doi: 10.1016/j.bbi.2010.12.008 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 5(1):64–79. doi: 10.1002/emmm.201201544 PubMedCentralPubMedGoogle Scholar
  69. 69.
    Butovsky O, Siddiqui S, Gabriely G, Lanser AJ, Dake B, Murugaiyan G, Doykan CE, Wu PM, Gali RR, Iyer LK, Lawson R, Berry J, Krichevsky AM, Cudkowicz ME, Weiner HL (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122(9):3063–3087. doi: 10.1172/JCI62636 PubMedCentralPubMedGoogle Scholar
  70. 70.
    Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW, Pellerin L, Magistretti PJ, Rothstein JD (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487(7408):443–448. doi: 10.1038/nature11314 PubMedCentralPubMedGoogle Scholar
  71. 71.
    Philips T, Bento-Abreu A, Nonneman A, Haeck W, Staats K, Geelen V, Hersmus N, Kusters B, Van Den Bosch L, Van Damme P, Richardson WD, Robberecht W (2013) Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain: J Neurol 136(Pt 2):471–482. doi: 10.1093/brain/aws339 Google Scholar
  72. 72.
    Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD (2000) NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci: Off J Soc Neurosci 20(17):6404–6412Google Scholar
  73. 73.
    Magnus T, Carmen J, Deleon J, Xue H, Pardo AC, Lepore AC, Mattson MP, Rao MS, Maragakis NJ (2008) Adult glial precursor proliferation in mutant SOD1G93A mice. Glia 56(2):200–208. doi: 10.1002/glia.20604 PubMedGoogle Scholar
  74. 74.
    Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2 + CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4):668–681. doi: 10.1016/j.neuron.2010.09.009 PubMedCentralPubMedGoogle Scholar
  75. 75.
    Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci. doi: 10.1038/nn.3357 Google Scholar
  76. 76.
    Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH, Attwell D (2011) Regulation of oligodendrocyte development and myelination by glucose and lactate. J Neurosci: Off J Soc Neurosci 31(2):538–548. doi: 10.1523/JNEUROSCI.3516-10.2011 Google Scholar
  77. 77.
    Perrie WT, Lee GT, Curtis EM, Sparke J, Buller JR, Rossi ML (1993) Changes in the myelinated axons of femoral nerve in amyotrophic lateral sclerosis. J Neural Transm Suppl 39:223–233PubMedGoogle Scholar
  78. 78.
    Keller AF, Gravel M, Kriz J (2009) Live imaging of amyotrophic lateral sclerosis pathogenesis: disease onset is characterized by marked induction of GFAP in Schwann cells. Glia 57(10):1130–1142. doi: 10.1002/glia.20836 PubMedGoogle Scholar
  79. 79.
    Turner BJ, Ackerley S, Davies KE, Talbot K (2010) Dismutase-competent SOD1 mutant accumulation in myelinating Schwann cells is not detrimental to normal or transgenic ALS model mice. Hum Mol Genet 19(5):815–824. doi: 10.1093/hmg/ddp550 PubMedGoogle Scholar
  80. 80.
    Lobsiger CS, Boillee S, McAlonis-Downes M, Khan AM, Feltri ML, Yamanaka K, Cleveland DW (2009) Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci USA 106(11):4465–4470. doi: 10.1073/pnas.0813339106 PubMedGoogle Scholar
  81. 81.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. doi: 10.1126/science.1134108 PubMedGoogle Scholar
  82. 82.
    Nishihira Y, Tan CF, Onodera O, Toyoshima Y, Yamada M, Morita T, Nishizawa M, Kakita A, Takahashi H (2008) Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116(2):169–182. doi: 10.1007/s00401-008-0385-z PubMedGoogle Scholar
  83. 83.
    Zhang H, Tan CF, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K (2008) TDP-43-immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol 115(1):115–122. doi: 10.1007/s00401-007-0285-7 PubMedGoogle Scholar
  84. 84.
    Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM, Clark CM, Grossman M, Miller BL, Trojanowski JQ, Lee VM (2007) TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuropathol Exp Neurol 66(3):177–183. doi: 10.1097/01.jnen.0000248554.45456.58 PubMedGoogle Scholar
  85. 85.
    Seilhean D, Cazeneuve C, Thuries V, Russaouen O, Millecamps S, Salachas F, Meininger V, Leguern E, Duyckaerts C (2009) Accumulation of TDP-43 and alpha-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol 118(4):561–573. doi: 10.1007/s00401-009-0545-9 PubMedGoogle Scholar
  86. 86.
    Swarup V, Phaneuf D, Dupre N, Petri S, Strong M, Kriz J, Julien JP (2011) Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways. J Exp Med 208(12):2429–2447. doi: 10.1084/jem.20111313 PubMedCentralPubMedGoogle Scholar
  87. 87.
    Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, Burr K, Haghi G, Story D, Nishimura AL, Carrasco MA, Phatnani HP, Shum C, Wilmut I, Maniatis T, Shaw CE, Finkbeiner S, Chandran S (2013) Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci USA. doi: 10.1073/pnas.1300398110 PubMedGoogle Scholar
  88. 88.
    Tong J, Huang C, Bi F, Wu Q, Huang B, Liu X, Li F, Zhou H, Xia XG (2013) Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats. EMBO J. doi: 10.1038/emboj.2013.122 Google Scholar
  89. 89.
    Diaper DC, Adachi Y, Lazarou L, Greenstein M, Simoes FA, Di Domenico A, Solomon DA, Lowe S, Alsubaie R, Cheng D, Buckley S, Humphrey DM, Shaw CE, Hirth F (2013) Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD. Hum Mol Genet. doi: 10.1093/hmg/ddt243 Google Scholar
  90. 90.
    Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29(16):2841–2857. doi: 10.1038/emboj.2010.143 PubMedGoogle Scholar
  91. 91.
    Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K, Roeber S, Kretzschmar HA, Cairns NJ, Neumann M (2011) Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 121(2):207–218. doi: 10.1007/s00401-010-0764-0 PubMedGoogle Scholar
  92. 92.
    Hewitt C, Kirby J, Highley JR, Hartley JA, Hibberd R, Hollinger HC, Williams TL, Ince PG, McDermott CJ, Shaw PJ (2010) Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 67(4):455–461. doi: 10.1001/archneurol.2010.52 PubMedGoogle Scholar
  93. 93.
    Robertson J, Bilbao J, Zinman L, Hazrati LN, Tokuhiro S, Sato C, Moreno D, Strome R, Mackenzie IR, Rogaeva E (2011) A novel double mutation in FUS gene causing sporadic ALS. Neurobiol Aging 32(3):553 e527–553 e530. doi: 10.1016/j.neurobiolaging.2010.05.015 Google Scholar
  94. 94.
    Yamamoto-Watanabe Y, Watanabe M, Okamoto K, Fujita Y, Jackson M, Ikeda M, Nakazato Y, Ikeda Y, Matsubara E, Kawarabayashi T, Shoji M (2010) A Japanese ALS6 family with mutation R521C in the FUS/TLS gene: a clinical, pathological and genetic report. J Neurol Sci 296(1–2):59–63. doi: 10.1016/j.jns.2010.06.008 PubMedGoogle Scholar
  95. 95.
    Del Bo R, Tiloca C, Pensato V, Corrado L, Ratti A, Ticozzi N, Corti S, Castellotti B, Mazzini L, Soraru G, Cereda C, D’Alfonso S, Gellera C, Comi GP, Silani V (2011) Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychia 82(11):1239–1243. doi: 10.1136/jnnp.2011.242313 Google Scholar
  96. 96.
    van Blitterswijk M, van Vught PW, van Es MA, Schelhaas HJ, van der Kooi AJ, de Visser M, Veldink JH, van den Berg LH (2012) Novel optineurin mutations in sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging 33(5):1016 e1011–1016 e1017. doi: 10.1016/j.neurobiolaging.2011.05.019 Google Scholar
  97. 97.
    Tumer Z, Bertelsen B, Gredal O, Magyari M, Nielsen KC, Lucamp, Gronskov K, Brondum-Nielsen K (2012) Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS. Neurobiol Aging 33(1):208 e201–208 e205. doi: 10.1016/j.neurobiolaging.2011.07.001 Google Scholar
  98. 98.
    Hattula K, Peranen J (2000) FIP-2, a coiled-coil protein, links huntingtin to rab8 and modulates cellular morphogenesis. Curr Biol: CB 10(24):1603–1606PubMedGoogle Scholar
  99. 99.
    Moreland RJ, Dresser ME, Rodgers JS, Roe BA, Conaway JW, Conaway RC, Hanas JS (2000) Identification of a transcription factor IIIA-interacting protein. Nuc Acids Res 28(9):1986–1993Google Scholar
  100. 100.
    Anborgh PH, Godin C, Pampillo M, Dhami GK, Dale LB, Cregan SP, Truant R, Ferguson SS (2005) Inhibition of metabotropic glutamate receptor signaling by the huntingtin-binding protein optineurin. J Biol Chem 280(41):34840–34848. doi: 10.1074/jbc.M504508200 PubMedGoogle Scholar
  101. 101.
    Sahlender DA, Roberts RC, Arden SD, Spudich G, Taylor MJ, Luzio JP, Kendrick-Jones J, Buss F (2005) Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol 169(2):285–295. doi: 10.1083/jcb.200501162 PubMedGoogle Scholar
  102. 102.
    Zhu G, Wu CJ, Zhao Y, Ashwell JD (2007) Optineurin negatively regulates TNFalpha- induced NF-kappaB activation by competing with NEMO for ubiquitinated RIP. Curr Biol: CB 17(16):1438–1443. doi: 10.1016/j.cub.2007.07.041 PubMedGoogle Scholar
  103. 103.
    del Toro D, Alberch J, Lazaro-Dieguez F, Martin-Ibanez R, Xifro X, Egea G, Canals JM (2009) Mutant huntingtin impairs post-Golgi trafficking to lysosomes by delocalizing optineurin/rab8 complex from the Golgi apparatus. Mol Biol Cell 20(5):1478–1492. doi: 10.1091/mbc.E08-07-0726 PubMedCentralPubMedGoogle Scholar
  104. 104.
    Kachaner D, Filipe J, Laplantine E, Bauch A, Bennett KL, Superti-Furga G, Israel A, Weil R (2012) Plk1-dependent phosphorylation of optineurin provides a negative feedback mechanism for mitotic progression. Mol Cell 45(4):553–566. doi: 10.1016/j.molcel.2011.12.030 PubMedGoogle Scholar
  105. 105.
    Sako W, Ito H, Yoshida M, Koizumi H, Kamada M, Fujita K, Hashizume Y, Izumi Y, Kaji R (2012) Nuclear factor kappa B expression in patients with sporadic amyotrophic lateral sclerosis and hereditary amyotrophic lateral sclerosis with optineurin mutations. Clin Neuropathol 31(6):418–423. doi: 10.5414/NP300493 PubMedGoogle Scholar
  106. 106.
    Ito H, Fujita K, Nakamura M, Wate R, Kaneko S, Sasaki S, Yamane K, Suzuki N, Aoki M, Shibata N, Togashi S, Kawata A, Mochizuki Y, Mizutani T, Maruyama H, Hirano A, Takahashi R, Kawakami H, Kusaka H (2011) Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Acta Neuropathol 121(4):555–557. doi: 10.1007/s00401-011-0809-z PubMedGoogle Scholar
  107. 107.
    Shaid S, Brandts CH, Serve H, Dikic I (2013) Ubiquitination and selective autophagy. Cell Death Differ 20(1):21–30. doi: 10.1038/cdd.2012.72 PubMedGoogle Scholar
  108. 108.
    Korac J, Schaeffer V, Kovacevic I, Clement AM, Jungblut B, Behl C, Terzic J, Dikic I (2013) Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. J Cell Sci 126(Pt 2):580–592. doi: 10.1242/jcs.114926 PubMedCentralPubMedGoogle Scholar
  109. 109.
    Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A (2009) Astroglia in dementia and Alzheimer’s disease. Cell Death Differ 16(3):378–385. doi: 10.1038/cdd.2008.172 PubMedGoogle Scholar
  110. 110.
    Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58(7):831–838. doi: 10.1002/glia.20967 PubMedGoogle Scholar
  111. 111.
    Yeh CY, Vadhwana B, Verkhratsky A, Rodriguez JJ (2011) Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer’s disease. ASN Neuro 3(5):271–279. doi: 10.1042/AN20110025 PubMedGoogle Scholar
  112. 112.
    Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, Sykova E, Rodriguez JJ (2012) Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat 221(3):252–262. doi: 10.1111/j.1469-7580.2012.01536.x PubMedGoogle Scholar
  113. 113.
    Bernstein HG, Steiner J, Bogerts B (2009) Glial cells in schizophrenia: pathophysiological significance and possible consequences for therapy. Exp Rev Neurother 9(7):1059–1071. doi: 10.1586/ern.09.59 Google Scholar
  114. 114.
    Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord: Drug Targ 6(3):219–233Google Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Chiara F. Valori
    • 1
  • Liliana Brambilla
    • 2
  • Francesca Martorana
    • 2
  • Daniela Rossi
    • 2
  1. 1.Department of NeuropathologyGerman Center for Neurodegenerative Diseases (DZNE)TübingenGermany
  2. 2.Laboratory for Research on Neurodegenerative DisordersIRCCS Fondazione Salvatore MaugeriPaviaItaly

Personalised recommendations