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


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.


Superoxide dismutase Inclusion GFAP Stellation Bystander 



Amyotrophic lateral sclerosis


Astrocytic medium


Bovine serum albumin




Days in vitro


Dulbecco’s Modified Eagle Medium


Enhanced green fluorescent protein


Endoplasmic reticulum


Familial amyotrophic lateral sclerosis


Fetal bovine serum


Golgi apparatus


Motor neuronsclu


Glial fibrillary acidic protein


Hanks Balanced Salt Solution


Minimum essential media


Mutant Cu/Zn superoxide dismutase


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


Normal donkey serum


Normal goat serum


Phosphate buffered saline




Cu/Zn superoxide dismutase


Tris buffered saline





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)


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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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