Mouse models of amyotrophic lateral sclerosis

After the discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial amyotrophic lateral sclerosis (ALS), several transgenic mouse lines have been generated with various forms of SOD1 mutants exhibiting different steady-state protein levels. Studies with mice suggest that the toxicity of mutant SOD1 is unrelated to copper-mediated catalysis but rather to formation of misfolded SOD1 species and aggregates. Multiple targets of damage by mutant SOD1 species have been proposed including mitochondria, proteasomes, and secretory pathways. Evidence for cytoskeletal involvement in ALS has also been provided from other mouse models such as mice with disrupted Als2 gene, with neurofilament disorganization or with defects in microtubule-based transport. This paper will review how transgenic mouse models have been used for understanding ALS pathogenic pathways and for pre-clinical drug testing.

Section editor:Wolfgang Wurst – Institute of Developmental Genetics, GSF Research Centre, Neuherberg, Germany