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The Cysteine (Cys) Residues Cys-6 and Cys-111 in Mutant Superoxide Dismutase 1 (SOD1) A4V Are Required for Induction of Endoplasmic Reticulum Stress in Amyotrophic Lateral Sclerosis

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A Correction to this article was published on 11 June 2020

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons. Between 12 and 20% of inherited cases and approximately 1–2% of all cases are caused by mutations in the gene encoding dismutase 1 (SOD1). Mutant SOD1 A4V (alanine to valine) induces endoplasmic reticulum (ER) stress, which is increasingly implicated as a pathway to motor neuron degeneration and death in ALS. However, it remains unclear how ER stress is induced by mutant SOD1 A4V. Previous studies have established that it is induced early in pathophysiology and it precedes the formation of mutant SOD1 inclusions. SOD1 contains four cysteine residues, two of which form an intra-subunit disulphide bond involving Cys-57 and Cys-146. The remaining two cysteines, Cys-6 and Cys-111, remain unpaired and have been implicated in mutant SOD1 aggregation. In this study, we examined the relationship between the SOD1 A4V cysteine residues and aggregation, ER stress induction and toxicity. We report here that mutation of Cys-6 and Cys-111 in mutant SOD1 A4V, but not Cys-57 or Cys-146, ameliorates ER stress, inclusion formation and apoptosis in neuronal cell lines. These results imply that protein misfolding, induced by Cys-6 and Cys-111, is required for these pathological events in neuronal cells.

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Change history

  • 11 June 2020

    The original version of this article unfortunately contained an error in Fig. 3. The image shown for “C57S” was incorrect

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Funding

This work is supported by The Australian National Health and Medical Research Council Project grants (1006141, 1030513, 1086887 and 1124005); Dementia Teams Research Grant (1095215); Fight MND Foundation; and Motor Neuron Disease Research Institute of Australia. EP was supported by an Australian Postgraduate Award scholarship.

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Authors and Affiliations

  1. Centre for MND Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia

    Emma R. Perri, Sonam Parakh, Marta Vidal, Prachi Mehta, Adam K. Walker & Julie D. Atkin

  2. Department of General Surgery, Monash Health, Melbourne, Victoria, Australia

    Yi Ma & Julie D. Atkin

  3. Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia

    Adam K. Walker

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  1. Emma R. Perri
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Correspondence to Julie D. Atkin.

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Perri, E.R., Parakh, S., Vidal, M. et al. The Cysteine (Cys) Residues Cys-6 and Cys-111 in Mutant Superoxide Dismutase 1 (SOD1) A4V Are Required for Induction of Endoplasmic Reticulum Stress in Amyotrophic Lateral Sclerosis. J Mol Neurosci 70, 1357–1368 (2020). https://doi.org/10.1007/s12031-020-01551-6

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