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Neurochemical Research

, Volume 43, Issue 1, pp 166–179 | Cite as

SOD1 Mutations Causing Familial Amyotrophic Lateral Sclerosis Induce Toxicity in Astrocytes: Evidence for Bystander Effects in a Continuum of Astrogliosis

  • Nicole Wallis
  • Chew L. Lau
  • Manal A. Farg
  • Julie D. Atkin
  • Philip M. BeartEmail author
  • Ross D. O’Shea
Original Paper

Abstract

Astrocytes contribute to the death of motor neurons via non-cell autonomous mechanisms of injury in amyotrophic lateral sclerosis (ALS). Since mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie the neuropathology of some forms of familial ALS, we explored how expression of mutant SOD1 protein A4V SOD1-EGFP affected the biology of secondary murine astrocytes. A4V SOD1-EGFP expressing astrocytes (72 h after transfection) displayed decreased mitochondrial activity (~45%) and l-glutamate transport (~25%), relative to cells expressing wild-type SOD1-EGFP. A4V SOD1-EGFP altered F-actin and Hoechst staining, indicative of cytoskeletal and nuclear changes, and altered GM130 labelling suggesting fragmentation of Golgi apparatus. SOD1 inclusion formation shifted from discrete to “punctate” over 72 h with A4V SOD1-EGFP more rapidly producing inclusions than G85R SOD1-EGFP, and forming more punctate aggregates. A4V, not wild-type SOD1-EGFP, exerted a substantial, time-dependent effect on GFAP expression, and ~60% of astrocytes became stellate and hypertrophic at 72 h. Spreading toxicity was inferred since at 72 h ~80% of bystander cells exhibited hypertrophy and stellation. This evidence favours mutant SOD1-containing astrocytes releasing destructive species that alter the biology of adjacent astrocytes. This panoply of mutant SOD1-induced destructive events favours recruitment of astrocytes to non-cell autonomous injury in ALS.

Keywords

Superoxide dismutase Inclusion GFAP Stellation Bystander 

Abbreviations

ALS

Amyotrophic lateral sclerosis

AM

Astrocytic medium

BSA

Bovine serum albumin

D-Asp

d-Aspartate

div

Days in vitro

DMEM

Dulbecco’s Modified Eagle Medium

EGFP

Enhanced green fluorescent protein

ER

Endoplasmic reticulum

FALS

Familial amyotrophic lateral sclerosis

FBS

Fetal bovine serum

GA

Golgi apparatus

MNs

Motor neuronsclu

GFAP

Glial fibrillary acidic protein

HBSS

Hanks Balanced Salt Solution

MEM

Minimum essential media

mSOD1

Mutant Cu/Zn superoxide dismutase

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NDS

Normal donkey serum

NGS

Normal goat serum

PBS

Phosphate buffered saline

PFA

Paraformaldehyde

SOD1

Cu/Zn superoxide dismutase

TBS

Tris buffered saline

WT

Wild-type

Notes

Acknowledgements

PMB is pleased to contribute a paper to this Special Issue honouring Kazuhiro Ikenaka who has been a colleague furthering the neurochemical cause internationally (ISN) and in the Asia-Pacific (APSN) for some 15 years. Supported by NH&MRC (Australia) Project Grant (#509319) and Fellowship (PMB). NW acknowledges receipt of Postgraduate Scholarship from the Bethlehem Griffiths Research Foundation. JDA was in receipt of support from NH&MRC Project Grant (#454749), Bethlehem Griffiths Research Foundation, Motor Neurone Disease Research Institute of Australia (MND RIA), Henry Roth Foundation grant and MND RIA Fellowship.

Compliance with Ethical Standards

Conflict of interest

The authors state no conflict of interest.

Supplementary material

11064_2017_2385_MOESM1_ESM.tif (451 kb)
Supplementary Figure 1—Anti-SOD1 immunoblot analysis of supernatant fractions from cell lysates post SOD1-EGFP transfection (10 μg/lane). Analysis demonstrated that cells transfected with a range of SOD1-EGFP species exhibited a ~50 kDa band representing hSOD1-EGFP on a background of 16 kDa mSOD1. Lane 1. control (EGFP alone) Lane 2. A4V SOD1-EGFP supernatant Lane 3. G93A SOD1-EGFP supernatant Lane 4. G85R SOD1-EGFP supernatant Lane 5. WT SOD1-EGFP supernatant (TIF 450 KB)

References

  1. 1.
    Shaw PJ, Williams TL, Slade JY, Eggett CJ, Ince PG (1999) Low expression of GluR2 AMPA receptor subunit protein by human motor neurons. Neuroreport 10:261–265CrossRefGoogle Scholar
  2. 2.
    Bar PR (2000) Motor neuron disease in vitro: the use of cultured motor neurons to study amyotrophic lateral sclerosis. Eur J Pharmacol 405:285–295CrossRefGoogle Scholar
  3. 3.
    Boillee S, Vande Velde C, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59CrossRefGoogle Scholar
  4. 4.
    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 312:1389–1392CrossRefGoogle Scholar
  5. 5.
    Rao SD, Weiss JH (2004) Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci 27:17–23CrossRefGoogle Scholar
  6. 6.
    Bruijn LI, Miller TM, Cleveland DW (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27:723–749CrossRefGoogle Scholar
  7. 7.
    Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ (2011) Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 122:657–671CrossRefGoogle Scholar
  8. 8.
    Barbeito LH, Pehar M, Cassina P, Vargas MR, Peluffo H, Viera L, Estevez AG, Beckman JS (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev 47:263–274CrossRefGoogle Scholar
  9. 9.
    Beckman JS, Estevez AG, Crow JP, Barbeito L (2001) Superoxide dismutase and the death of motoneurons in ALS. Trends Neurosci 24:S15-20CrossRefGoogle Scholar
  10. 10.
    Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS (1997) Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem 69:1936–1944CrossRefGoogle Scholar
  11. 11.
    Turner BJ, Talbot K (2008) Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 85:94–134CrossRefGoogle Scholar
  12. 12.
    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 18:327–338CrossRefGoogle Scholar
  13. 13.
    Kato S (2008) Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Acta Neuropathol 115:97–114CrossRefGoogle Scholar
  14. 14.
    Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, Schoenfeld DA, Hosler BA, Horvitz HR, Brown RH (1997) Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol 41:210–221CrossRefGoogle Scholar
  15. 15.
    Valentine JS, Hart PJ (2003) Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 100:3617–3622CrossRefGoogle Scholar
  16. 16.
    Kuo JJ, Schonewille M, Siddique T, Schults AN, Fu R, Bar PR, Anelli R, Heckman CJ, Kroese AB (2004) Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice. J Neurophysiol 91:571–575CrossRefGoogle Scholar
  17. 17.
    Pambo-Pambo A, Durand J, Gueritaud JP (2009) Early excitability changes in lumbar motoneurons of transgenic SOD1G85R and SOD1G(93A-Low) mice. J Neurophysiol 102:3627–3642CrossRefGoogle Scholar
  18. 18.
    Pieri M, Albo F, Gaetti C, Spalloni A, Bengtson CP, Longone P, Cavalcanti S, Zona C (2003) Altered excitability of motor neurons in a transgenic mouse model of familial amyotrophic lateral sclerosis. Neurosci Lett 351:153–156CrossRefGoogle Scholar
  19. 19.
    Jonsson PA, Ernhill K, Andersen PM, Bergemalm D, Brannstrom T, Gredal O, Nilsson P, Marklund SL (2004) Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis. Brain 127:73–88CrossRefGoogle Scholar
  20. 20.
    Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brannstrom T, Rehnmark A, Marklund SL (2006) Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models. J Neurosci 26:4147–4154CrossRefGoogle Scholar
  21. 21.
    Kanekura K, Hashimoto Y, Niikura T, Aiso S, Matsuoka M, Nishimoto I (2004) Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. J Biol Chem 279:19247–19256CrossRefGoogle Scholar
  22. 22.
    Tiwari A, Xu Z, Hayward LJ (2005) Aberrantly increased hydrophobicity shared by mutants of Cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. J Biol Chem 280:29771–29779CrossRefGoogle Scholar
  23. 23.
    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 10:608–614CrossRefGoogle Scholar
  24. 24.
    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 10:615–622CrossRefGoogle Scholar
  25. 25.
    Vargas MR, Pehar M, Diaz-Amarilla PJ, Beckman JS, Barbeito L (2008) Transcriptional profile of primary astrocytes expressing ALS-linked mutant SOD1. J Neurosci Res 86:3515–3525CrossRefGoogle Scholar
  26. 26.
    Kobatake Y, Sakai H, Tsukui T, Yamato O, Kohyama M, Sasaki J, Kato S, Urushitani M, Maeda S, Kamishina H (2017) Localization of a mutant SOD1 protein in E40K-heterozygous dogs: implications for non-cell-autonomous pathogenesis of degenerative myelopathy. J Neurol Sci 372:369–378CrossRefGoogle Scholar
  27. 27.
    Ilieva H, Polymenidou M, Cleveland DW (2009) Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol 187:761–772CrossRefGoogle Scholar
  28. 28.
    Trias E, Ibarburu S, Barreto-Nunez R, Barbeito L (2017) Significance of aberrant glial cell phenotypes in pathophysiology of amyotrophic lateral sclerosis. Neurosci Lett 636:27–31CrossRefGoogle Scholar
  29. 29.
    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 108:18126–18131CrossRefGoogle Scholar
  30. 30.
    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 99:1604–1609CrossRefGoogle Scholar
  31. 31.
    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 and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828CrossRefGoogle Scholar
  32. 32.
    Hensley K, Abdel-Moaty H, Hunter J, Mhatre M, Mou S, Nguyen K, Potapova T, Pye QN, Qi M, Rice H, Stewart C, Stroukoff K, West M (2006) Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation. J Neuroinflammation 3:2CrossRefGoogle Scholar
  33. 33.
    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 103:16021–16026CrossRefGoogle Scholar
  34. 34.
    Lobsiger CS, Cleveland DW (2007) Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci 10:1355–1360CrossRefGoogle Scholar
  35. 35.
    Rossi D, Volterra A (2009) Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull 80:224–232CrossRefGoogle Scholar
  36. 36.
    Staats KA, Van Den Bosch L (2009) Astrocytes in amyotrophic lateral sclerosis: direct effects on motor neuron survival. J Biol Phys 35:337–346CrossRefGoogle Scholar
  37. 37.
    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 9:108–118CrossRefGoogle Scholar
  38. 38.
    Bristol LA, Rothstein JD (1996) Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 39:676–679CrossRefGoogle Scholar
  39. 39.
    Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689CrossRefGoogle Scholar
  40. 40.
    Goursaud S, Focant MC, Berger JV, Nizet Y, Maloteaux JM, Hermans E (2011) The VPAC2 agonist peptide histidine isoleucine (PHI) up-regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1G93A) by inhibiting caspase-3 mediated inactivation of GLT-1a. Faseb J 25:3674–3686CrossRefGoogle Scholar
  41. 41.
    Cleveland DW (1999) From Charcot to SOD1: mechanisms of selective motor neuron death in ALS. Neuron 24:515–520CrossRefGoogle Scholar
  42. 42.
    O’Shea RD, Lau CL, Farso MC, Diwakarla S, Zagami CJ, Svendsen BB, Feeney SJ, Callaway JK, Jones NM, Pow DV, Danbolt NC, Jarrott B, Beart PM (2006) Effects of lipopolysaccharide on glial phenotype and activity of glutamate transporters: evidence for delayed up-regulation and redistribution of GLT-1. Neurochem Int 48:604–610CrossRefGoogle Scholar
  43. 43.
    Moldrich RX, Aprico K, Diwakarla S, O’Shea RD, Beart PM (2002) Astrocyte mGlu(2/3)-mediated cAMP potentiation is calcium sensitive: studies in murine neuronal and astrocyte cultures. Neuropharmacology 43:189–203CrossRefGoogle Scholar
  44. 44.
    Turner BJ, Atkin JD, Farg MA, Zang DW, Rembach A, Lopes EC, Patch JD, Hill AF, Cheema SS (2005) Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. J Neurosci 25:108–117CrossRefGoogle Scholar
  45. 45.
    Lau CL, Beart PM, O’Shea RD (2010) Transportable and non-transportable inhibitors of L-glutamate uptake produce astrocytic stellation and increase EAAT2 cell surface expression. Neurochem Res 35:735–742CrossRefGoogle Scholar
  46. 46.
    Zagami CJ, O’Shea RD, Lau CL, Cheema SS, Beart PM (2005) Regulation of glutamate transporters in astrocytes: evidence for a relationship between transporter expression and astrocytic phenotype. Neurotox Res 7:143–149CrossRefGoogle Scholar
  47. 47.
    Aprico K, Beart PM, Crawford D, O’Shea RD (2004) Binding and transport of [3H](2S,4R)-4-methylglutamate, a new ligand for glutamate transporters, demonstrate labeling of EAAT1 in cultured murine astrocytes. J Neurosci Res 75:751–759CrossRefGoogle Scholar
  48. 48.
    Boido M, Buschini E, Piras A, Spigolon G, Valsecchi V, Mazzini L, Vercelli A (2012) Advantages and Pitfalls in Experimental Models Of ALS. In: Maurer PM (ed) Amyotrophic lateral sclerosis. InTech, New York. doi:  https://doi.org/10.5772/31380 CrossRefGoogle Scholar
  49. 49.
    Wallis N, Zagami CJ, Beart PM, O’Shea RD (2012) Combined excitotoxic-oxidative stress and the concept of non-cell autonomous pathology of ALS: Insights into motoneuron axonopathy and astrogliosis. Neurochem Int 61:523–530CrossRefGoogle Scholar
  50. 50.
    Holmes BB, Diamond MI (2012) Cellular mechanisms of protein aggregate propagation. Curr Opin Neurol 25:721–726CrossRefGoogle Scholar
  51. 51.
    Tortarolo M, Crossthwaite AJ, Conforti L, Spencer JP, Williams RJ, Bendotti C, Rattray M (2004) Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1: lack of involvement of oxidative stress. J Neurochem 88:481–493CrossRefGoogle Scholar
  52. 52.
    Beart PM, O’Shea RD (2007) Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150:5–17CrossRefGoogle Scholar
  53. 53.
    Coussee E, De Smet P, Bogaert E, Elens I, Van Damme P, Willems P, Koopman W, Van Den Bosch L, Callewaert G (2011) G37R SOD1 mutant alters mitochondrial complex I activity, Ca(2+) uptake and ATP production. Cell Calcium 49:217–225CrossRefGoogle Scholar
  54. 54.
    Zagami CJ, Beart PM, Wallis N, Nagley P, O’Shea RD (2009) Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis. Glia 57:119–135CrossRefGoogle Scholar
  55. 55.
    Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281:30152–30165CrossRefGoogle Scholar
  56. 56.
    Nagley P, Higgins GC, Atkin JD, Beart PM (2010) Multifaceted deaths orchestrated by mitochondria in neurones. Biochim Biophys Acta 1802:167–185CrossRefGoogle Scholar
  57. 57.
    Nakagomi S, Barsoum MJ, Bossy-Wetzel E, Sutterlin C, Malhotra V, Lipton SA (2008) A Golgi fragmentation pathway in neurodegeneration. Neurobiol Dis 29:221–231CrossRefGoogle Scholar
  58. 58.
    Mourelatos Z, Gonatas NK, Stieber A, Gurney ME, Dal Canto MC (1996) The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc Natl Acad Sci USA 93:5472–5477CrossRefGoogle Scholar
  59. 59.
    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 177:114–123CrossRefGoogle Scholar
  60. 60.
    Liazoghli D, Perreault S, Micheva KD, Desjardins M, Leclerc N (2005) Fragmentation of the Golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons. Am J Pathol 166:1499–1514CrossRefGoogle Scholar
  61. 61.
    Atkin JD, Farg MA, Soo KY, Walker AK, Halloran M, Turner BJ, Nagley P, Horne MK (2014) Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis. J Neurochem 129:190–204CrossRefGoogle Scholar
  62. 62.
    Soo KY, Atkin JD, Horne MK, Nagley P (2009) Recruitment of mitochondria into apoptotic signaling correlates with the presence of inclusions formed by amyotrophic lateral sclerosis-associated SOD1 mutations. J Neurochem 108:578–590CrossRefGoogle Scholar
  63. 63.
    Pasinelli P, Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7:710–723CrossRefGoogle Scholar
  64. 64.
    Mucke L, Oldstone MB, Morris JC, Nerenberg MI (1991) Rapid activation of astrocyte-specific expression of GFAP-lacZ transgene by focal injury. New Biol 3:465–474PubMedGoogle Scholar
  65. 65.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35CrossRefGoogle Scholar
  66. 66.
    Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan TE, Pekny M (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24:5016–5021CrossRefGoogle Scholar
  67. 67.
    Vargas MR, Pehar M, Cassina P, Beckman JS, Barbeito L (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem 97:687–696CrossRefGoogle Scholar
  68. 68.
    Liddelow S, Barres B (2015) SnapShot: astrocytes in health and disease. Cell 162:1170–1170.e1171CrossRefGoogle Scholar
  69. 69.
    Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391–6410CrossRefGoogle Scholar
  70. 70.
    Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98CrossRefGoogle Scholar
  71. 71.
    Migheli A, Atzori C, Piva R, Tortarolo M, Girelli M, Schiffer D, Bendotti C (1999) Lack of apoptosis in mice with ALS. Nat Med 5:966–967CrossRefGoogle Scholar
  72. 72.
    Sasaki S, Komori T, Iwata M (2000) Excitatory amino acid transporter 1 and 2 immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol 100:138–144CrossRefGoogle Scholar
  73. 73.
    Fitch MT, Silver J (2008) CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol 209:294–301CrossRefGoogle Scholar
  74. 74.
    Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL 3rd, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Nicole Wallis
    • 1
    • 2
    • 3
  • Chew L. Lau
    • 1
  • Manal A. Farg
    • 1
    • 4
  • Julie D. Atkin
    • 1
    • 4
    • 5
  • Philip M. Beart
    • 1
    • 2
    • 7
    Email author
  • Ross D. O’Shea
    • 6
  1. 1.Neurodegeneration, Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  2. 2.Department of PharmacologyUniversity of MelbourneParkvilleAustralia
  3. 3.Orygen, The National Centre of Excellence in Youth Mental HealthParkvilleAustralia
  4. 4.Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityBundooraAustralia
  5. 5.Department of Biomedical SciencesMacquarie UniversityNorth RydeAustralia
  6. 6.Department of Physiology, Anatomy and MicrobiologyLa Trobe UniversityBundooraAustralia
  7. 7.Melbourne Brain Centre, Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia

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