SOD1 Mutations Causing Familial Amyotrophic Lateral Sclerosis Induce Toxicity in Astrocytes: Evidence for Bystander Effe
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ORIGINAL PAPER
SOD1 Mutations Causing Familial Amyotrophic Lateral Sclerosis Induce Toxicity in Astrocytes: Evidence for Bystander Effects in a Continuum of Astrogliosis Nicole Wallis1,2,3 · Chew L. Lau1 · Manal A. Farg1,4 · Julie D. Atkin1,4,5 · Philip M. Beart1,2,7 · Ross D. O’Shea6
Received: 1 May 2017 / Revised: 11 August 2017 / Accepted: 14 August 2017 © Springer Science+Business Media, LLC 2017
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 Nicole Wallis, Chew L. Lau, Philip M. Beart and Ross D. O’Shea have contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s11064-017-2385-7) contains supplementary material, which is available to authorized users. * Philip M. Beart [email protected] 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, 144 Royal Parade, Parkville, VIC 3010, Australia
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, timedependent 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 scler
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