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The Journal of Neuroscience, April 19, 2006, 26(16):4147-4154; doi:10.1523/JNEUROSCI.5461-05.2006

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Neurobiology of Disease
Overloading of Stable and Exclusion of Unstable Human Superoxide Dismutase-1 Variants in Mitochondria of Murine Amyotrophic Lateral Sclerosis Models

Daniel Bergemalm,¹ P. Andreas Jonsson,¹ Karin S. Graffmo,² Peter M. Andersen,³ Thomas Brännström,² Anna Rehnmark,¹ and Stefan L. Marklund¹

Department of Medical Biosciences, ¹Clinical Chemistry and ²Pathology and ³Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 85 Umeå, Sweden

Correspondence should be addressed to Stefan L. Marklund, Department of Medical Biosciences, Clinical Chemistry, Umeå University, SE-901 85 Umeå, Sweden. Email: stefan.marklund{at}medbio.umu.se

Mutants of human superoxide dismutase-1 (hSOD1) cause amyotrophic lateral sclerosis (ALS), and mitochondria are thought to be primary targets of the cytotoxic action. The high expression rates of hSOD1s in transgenic ALS models give high levels of the stable mutants G93A and D90A as well as the wild-type human enzyme, significant proportions of which lack Cu and the intrasubunit disulfide bond. The endogenous murine SOD1 (mSOD1) also lacks Cu and is disulfide reduced but is active and oxidized in mice expressing the low-level unstable mutants G85R and G127insTGGG. The possibility that the molecular alterations may cause artificial loading of the stable hSOD1s into mitochondria was explored. Approximately 10% of these hSOD1s were localized to mitochondria, reaching levels 100-fold higher than those of mSOD1 in control mice. There was no difference between brain and spinal cord and between stable mutants and the wild-type hSOD1. mSOD1 was increased fourfold in mitochondria from high-level hSOD1 mice but was normal in those with low levels, suggesting that the Cu deficiency and disulfide reduction cause mitochondrial overloading. The levels of G85R and G127insTGGG mutant hSOD1s in mitochondria were 100- and 1000-fold lower than those of stable mutants. Spinal cords from symptomatic mice contained hSOD1 aggregates covering the entire density gradient, which could contaminate isolated organelle fractions. Thus, high hSOD1 expression rates can cause artificial loading of mitochondria. Unstable low-level hSOD1s are excluded from mitochondria, indicating other primary locations of injury. Such models may be preferable for studies of ALS pathogenesis.

Key words: amyotrophic lateral sclerosis; mitochondria; superoxide dismutase; transgenic mice; Cu; disulfide bond

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Received Dec. 21, 2005; revised Feb. 23, 2006; accepted March 8, 2006.

Correspondence should be addressed to Stefan L. Marklund, Department of Medical Biosciences, Clinical Chemistry, Umeå University, SE-901 85 Umeå, Sweden. Email: stefan.marklund{at}medbio.umu.se

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