SOD1 Mutations Causing Familial Amyotrophic Lateral Sclerosis Induce Toxicity in Astrocytes: Evidence for Bystander Effects in a Continuum of Astrogliosis |
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Authors: | Nicole Wallis Chew L. Lau Manal A. Farg Julie D. Atkin Philip M. Beart Ross D. O’Shea |
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Affiliation: | 1.Neurodegeneration, Florey Institute of Neuroscience and Mental Health,Parkville,Australia;2.Department of Pharmacology,University of Melbourne,Parkville,Australia;3.Orygen, The National Centre of Excellence in Youth Mental Health,Parkville,Australia;4.Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science,La Trobe University,Bundoora,Australia;5.Department of Biomedical Sciences,Macquarie University,North Ryde,Australia;6.Department of Physiology, Anatomy and Microbiology,La Trobe University,Bundoora,Australia;7.Melbourne Brain Centre, Florey Institute of Neuroscience and Mental Health,University of Melbourne,Parkville,Australia |
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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. |
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