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. Beart, Ross D. O’Shea

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages166-179
Number of pages14
JournalNeurochemical Research
Volume43
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

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Bystander Effect
Astrocytes
Toxicity
Mutation
Amyotrophic Lateral Sclerosis
Gene encoding
Wounds and Injuries
Golgi Apparatus
Motor Neurons
Mutant Proteins
Amyotrophic lateral sclerosis 1
Labeling
Hypertrophy
Neurons
Transfection
Actins
Glutamic Acid
Cells
Staining and Labeling

Keywords

  • Bystander
  • GFAP
  • Inclusion
  • Stellation
  • Superoxide dismutase

Cite this

Wallis, Nicole ; Lau, Chew L. ; Farg, Manal A. ; Atkin, Julie D. ; Beart, Philip M. ; O’Shea, Ross D. / SOD1 mutations causing familial amyotrophic lateral sclerosis induce toxicity in astrocytes : evidence for bystander effects in a continuum of astrogliosis. In: Neurochemical Research. 2018 ; Vol. 43, No. 1. pp. 166-179.
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SOD1 mutations causing familial amyotrophic lateral sclerosis induce toxicity in astrocytes : evidence for bystander effects in a continuum of astrogliosis. / Wallis, Nicole; Lau, Chew L.; Farg, Manal A.; Atkin, Julie D.; Beart, Philip M.; O’Shea, Ross D.

In: Neurochemical Research, Vol. 43, No. 1, 01.01.2018, p. 166-179.

Research output: Contribution to journalArticleResearchpeer-review

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