[Implications of successful immunotherapy in ALS model mice]

Recent progress in clinical genetics has explored various mutations or associated genes in both familial and sporadic amyotrophic lateral sclerosis (ALS). Mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS, and mutant SOD1 transgenic mice are still regarded as the best ALS model animals for the first step of therapeutic estimation. Emerging evidence indicates that SOD1 is secreted in spite of lacking translocation signal. We previously found chromogranins interact with ALS-linked SOD1 mutants, but not with wild-type, and promote the secretion SOD1 mutants. Moreover, extracellular SOD1 mutant activates microglia and kills motor neuron. This scenario may well explain non-cell-autonomous fashion of mutant SOD1-induced pathology in ALS. Accordingly, vaccination targeting extracellular SOD1 mutants significantly delays disease onset and prolongs lifespan of mutant SOD1 transgenic mice. Moreover, intraventricular application of ant-mutant SOD1 antibody also showed beneficial effect. In this review, the rationale between protein misfolding of mutant SOD1 and effect of immunization is delineated and further perspective of this non-invasive treatment not only for mutant SOD1 but also for sporadic ALS is discussed.