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Cu and Zn in superoxide dismutase and amyotrophic lateral sclerosis

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. The disease is rapidly progressive with a mean survival of three to five years because of the lack of effective therapy. The underlying causes are still elusive but the mechanisms are multifactorial. Several genes have been associated with ALS, the first of which is the gene coding the copper zinc superoxide dismutase SOD1 or CuZnSOD.

Using cellular models, we studied the metallation state of SOD1 by coupling a separative, non denaturating technique (isoelectric focusing, IEF) and methods for analysis of metals by ion beam analysis (AIFIRA, CENBG – Biochimie (2009), 91, 1324-1327 and Electrophoresis (2015), 36, 2482-2488) and by synchrotron radiation (ESRF – JAAS (2008), 23, 1083-1088 and SOLEIL – Electrophoresis (2012), 33, 1276-1281).

These analytical achievements helped us to reveal the existence of an equilibrium between several SOD1 isoforms characterized by different Cu/Zn ratio and charge state. We showed that SOD1 mutants are associated with an increase of the isoelectric point (pI) of active isoforms. It results in a decrease of their net charge that would facilitate their aggregation and toxicity. This effect is also correlated with the metallation state since the decrease of the net charge is more pronounced for isoforms with lower Cu/Zn ratio.

Figure 1. pI measurements of SOD1 in wild-type (hWT) and mutants linked to ALS (A4V, G93A, D125H). Note the increase of pI in mutants (Electrophoresis (2015), 36, 2482-2488).

Figure 2. Cu/Zn ratio in isoforms according their isoelectric point. For a given genotype, the SOD1 isoforms have different Cu/Zn ratio and the increase of pI is correlated to a decrease of Cu/Zn. hWT is the wild-type SOD1 while A4V, G93A and D125H are mutants linked to familial cases of ALS (Electrophoresis (2015), 36, 2482-2488).


IPREM Institut des Sciences Analytiques et Physico-Chimique pour l’Environnement et les Matériaux. Unité Mixte de Recherche CNRS / UPPA (UMR 5254).

Department of Chemistry and Biochemistry, UCLA University of California at Los Angeles, USA


Reduced net charge and heterogeneity of pI isoforms in familial amyotrophic lateral sclerosis mutants of copper/zinc superoxide dismutase.
Roudeau S, Chevreux S, Carmona A, Ortega R. (2015), Electrophoresis, 2015 Jun 17. doi: 10.1002/elps.201500187. Epub ahead of print [pubmed] [link]

Coupling of native IEF and Extended X-ray Absorption Fine Structure to characterize zinc binding sites from pI isoforms of SOD1 and A4V pathogenic mutant
Chevreux S., Llorens I., Solari P.-L., Roudeau S., Devès G., Carmona A., Testemale D., Hazemann J.L., Ortega R. (2012), Electrophoresis, 33, 1276-1281 [pubmed] [link]

Multimodal analysis of metals in copper-zinc superoxide dismutase isoforms separated on electrophoresis gels
Chevreux S., Roudeau S., Fraysse A., Carmona A., Devès G., Solari P.-L., Mounicou S., Lobinski R., Ortega R. (2009), Biochimie 91, 1324-1327. [pubmed] [link]

EXAFS analysis of a human Cu,Zn SOD isoform focused using non-denaturing gel electrophoresis
Chevreux S., Solari P.L., Roudeau S., Devès G., Alliot I.,Testemale J.L., Hazemann J.L. Ortega R. (2009), Journal of Physics IV, 190, 012205. [link]

Direct speciation of metals in copper-zinc superoxide dismutase isoforms on electrophoresis gels using X-ray absorption near edge structure
Chevreux S., Roudeau S., Fraysse A., Carmona A., Devès G., Solari P.L., Weng T.C., Ortega R. (2008), Journal of Analytical Atomic Spectrometry, 23, 1117-1120. [link]