Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex Cu-II(atsm) tested for therapeutic efficacy in mice expressing SOD1(G93A) on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1(G93A) mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the Cu-II(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with Cu-II(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for Cu-II(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.
|Authors||Hilton, James B.; Mercer, Stephen W.; Lim, Nastasia K. H.; Faux, Noel G.; Buncic, Gojko; Beckman, Joseph S.; Roberts, Blaine R.; Donnelly, Paul S.; White, Anthony R.; Crouch, Peter J.|
|Funding Body||National Health and Medical Research Council|