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

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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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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

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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.

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Author notes

  1. Nicole Wallis, Chew L. Lau, Philip M. Beart and Ross D. O’Shea have contributed equally to this work.

Authors and Affiliations

  1. Neurodegeneration, Florey Institute of Neuroscience and Mental Health, Parkville, Australia

    Nicole Wallis, Chew L. Lau, Manal A. Farg, Julie D. Atkin & Philip M. Beart

  2. Department of Pharmacology, University of Melbourne, Parkville, Australia

    Nicole Wallis & Philip M. Beart

  3. Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Australia

    Nicole Wallis

  4. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia

    Manal A. Farg & Julie D. Atkin

  5. Department of Biomedical Sciences, Macquarie University, North Ryde, Australia

    Julie D. Atkin

  6. Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Australia

    Ross D. O’Shea

  7. Melbourne Brain Centre, Florey Institute of Neuroscience and Mental Health, University of Melbourne, 144 Royal Parade, Parkville, VIC, 3010, Australia

    Philip M. Beart

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  1. Nicole Wallis
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11064_2017_2385_MOESM1_ESM.tif

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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Wallis, N., Lau, C.L., Farg, M.A. et al. SOD1 Mutations Causing Familial Amyotrophic Lateral Sclerosis Induce Toxicity in Astrocytes: Evidence for Bystander Effects in a Continuum of Astrogliosis. Neurochem Res 43, 166–179 (2018). https://doi.org/10.1007/s11064-017-2385-7

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