Wild-type human SOD1 overexpression does not accelerate motor neuron disease in mice expressing murine Sod1G86R

Approximately 10% of the cases of amyotrophic lateral sclerosis (ALS) are inherited, with the majority of identified linkages in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies showed that human wild-type SOD1 (SOD1WT) overexpression accelerated disease in mice expressing human SOD1 mutants linked to ALS. However, there is a controversy whether the exacerbation mechanism occurs through coaggregation of human SOD1WT with SOD1 mutants, stabilization by SOD1WT of toxic soluble SOD1 species, or conversion of SOD1WT into toxic species through oxidative damage. To further address whether the exacerbation of disease requires misfolding, modifications, and/or interaction of SOD1WT with pathogenic forms of SOD1 species, we have studied the effect of human SOD1WT overexpression in mice expressing the murine mutant Sod1G86R. Surprisingly, unlike a previous report with SOD1G85R mice, SOD1WT overexpression did not affect the life span of Sod1G86R mice. Our analysis of spinal cord extracts revealed a lack of heterodimerization or aggregation between human SOD1WT and mouse Sod1G86R proteins. Moreover, there was no evidence of conversion of SOD1WT into misfolded or abnormal SOD1 isoforms based on immunoreactivity with monoclonal antibodies specific to misfolded forms of SOD1 mutants and on analysis of SOD1 isoforms after two-dimensional gel electrophoresis. We conclude that a direct interaction between wild type and mutant forms of SOD1 is required for exacerbation of ALS disease by SOD1WT protein.