Oxidative Modifications of Cu, Zn-Superoxide Dismutase (SOD1) – The Relevance to Amyotrophic Lateral Sclerosis (ALS)

Nagano, Seiichi

doi:10.5772/32476

Amyotrophic Lateral Sclerosis 2012

DOI: 10.5772/32476

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Oxidative Modifications of Cu, Zn-Superoxide Dismutase (SOD1) – The Relevance to Amyotrophic Lateral Sclerosis (ALS)

Seiichi Nagano¹

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2013

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Cupric Ions Induce the Oxidation and Trigger the Aggregation of Human Superoxide Dismutase 1

Cheng

Xie

et al. 2013

PLoS ONE

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BackgroundAmyotrophic lateral sclerosis (ALS), partly caused by the mutations and aggregation of human copper, zinc superoxide dismutase (SOD1), is a fatal degenerative disease of motor neurons. Because SOD1 is a major copper-binding protein present at relatively high concentration in motor neurons and copper can be a harmful pro-oxidant, we want to know whether aberrant copper biochemistry could underlie ALS pathogenesis. In this study, we have investigated and compared the effects of cupric ions on the aggregation of ALS-associated SOD1 mutant A4V and oxidized wild-type SOD1.Methodology/Principal FindingsAs revealed by 90° light scattering, dynamic light scattering, SDS-PAGE, and atomic force microscopy, free cupric ions in solution not only induce the oxidation of either apo A4V or Zn2-A4V and trigger the oligomerization and aggregation of oxidized A4V under copper-mediated oxidative conditions, but also trigger the aggregation of non-oxidized form of such a pathogenic mutant. As evidenced by mass spectrometry and SDS-PAGE, Cys-111 is a primary target for oxidative modification of pathological human SOD1 mutant A4V by either excess Cu2+ or hydrogen peroxide. The results from isothermal titration calorimetry show that A4V possesses two sets of independent binding sites for Cu2+: a moderate-affinity site (106 M-1) and a high-affinity site (108 M-1). Furthermore, Cu2+ binds to wild-type SOD1 oxidized by hydrogen peroxide in a way similar to A4V, triggering the aggregation of such an oxidized form.Conclusions/SignificanceWe demonstrate that excess cupric ions induce the oxidation and trigger the aggregation of A4V SOD1, and suggest that Cu2+ plays a key role in the mechanism of aggregation of both A4V and oxidized wild-type SOD1. A plausible model for how pathological SOD1 mutants aggregate in ALS-affected motor neurons with the disruption of copper homeostasis has been provided.

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Cupric Ions Induce the Oxidation and Trigger the Aggregation of Human Superoxide Dismutase 1

Cheng

Xie

et al. 2013

PLoS ONE

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Oxidative Modifications of Cu, Zn-Superoxide Dismutase (SOD1) – The Relevance to Amyotrophic Lateral Sclerosis (ALS)

Cited by 1 publication

References 52 publications

Cupric Ions Induce the Oxidation and Trigger the Aggregation of Human Superoxide Dismutase 1

Cupric Ions Induce the Oxidation and Trigger the Aggregation of Human Superoxide Dismutase 1

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