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The perplexing role of copper-zinc superoxide dismutase in amyotrophic lateral sclerosis (Lou Gehrig's disease)

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Abstract

The existence of a link between some cases of familial amyotrophic lateral sclerosis (FALS) and copper-zinc superoxide dismutase (CuZnSOD) has been understood for almost a decade. However, beyond the fact that mutations in CuZnSOD cause FALS by a toxic gain of function, the mechanism whereby specific mutations in the protein structure result in development of the disease has remained almost a complete mystery to date. We have undertaken a critical survey of in vitro characteristics of over 30 of the 90 different CuZnSOD mutant proteins that are known to cause FALS in order to determine the differences that exist between mutant and wild-type properties. As-isolated metal content analysis, SOD activity assays, and thermal stability determinations of a significant fraction of the mutants show that the FALS mutant SOD proteins can be classified distinctly into one of two groups. Members of the first group, termed wild-type-like, have physical properties and enzymatic activities that are strikingly similar to those of wild-type CuZnSOD. The second group, however, show aberrant metal content in the as-isolated forms, compromised SOD activities, and unusual DSC thermoscans. All mutations in the members of this second group occur in or near the metal binding sites of the protein and thus they are termed metal binding region mutants. We have also compared the relative rates of self-inactivation caused by reaction of the wild-type protein and several FALS-linked CuZnSOD mutants with hydrogen peroxide, as a measure of relative peroxidative activities. Results and implications of the role of CuZnSOD in FALS are discussed.

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Abbreviations

ALS:

amyotrophic lateral sclerosis

DSC:

differential scanning calorimetry

FALS:

familial ALS

ICP-MS:

inductively coupled plasma mass spectrometry

POBN:

α-(pyridyl 4-N-oxide) N-tert-butyl nitrone

SOD1 or CuZnSOD:

copper-zinc superoxide dismutase protein, product of the sod1 gene

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Acknowledgements

We thank Jorge Rodriguez and Dr. Edith Gralla for helpful comments on this manuscript. We also thank Dr. P. John Hart at the University of Texas Health Science Center at San Antonio and Dr. Lawrence Hayward at the University of Massachusetts Medical School for many scientific discussions about ALS and SOD. Figures 2 and 3 were kindly provided by Dr. P. John Hart. This work was supported by grants from the ALS Association and National Institutes of Health Grant GM28222.

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  1. Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095-1569, USA

    Soshanna Zittin Potter & Joan Selverstone Valentine

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  1. Soshanna Zittin Potter
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  2. Joan Selverstone Valentine
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Correspondence to Joan Selverstone Valentine.

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Potter, S.Z., Valentine, J.S. The perplexing role of copper-zinc superoxide dismutase in amyotrophic lateral sclerosis (Lou Gehrig's disease). J Biol Inorg Chem 8, 373–380 (2003). https://doi.org/10.1007/s00775-003-0447-6

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