ALS pathogenesis: recent insights from genetics and mouse models.

For the vast majority of cases of amyotrophic lateral sclerosis (ALS) the etiology remains unknown. After the discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial ALS, several transgenic mouse lines have been generated with various forms of SOD1 mutants overexpressed at different levels. Studies with these mice yielded complex results with multiple targets of damage in disease including mitochondria, proteasomes, and secretory pathways. Many unexpected discoveries were made. For instance, the toxicity of mutant SOD1 seems unrelated to copper-mediated catalysis but rather to formation of misfolded SOD1 species and aggregates. Transgenic studies revealed a potential role of wtSOD1 in exacerbating mutant SOD1-mediated disease. Another key finding came from chimeric mouse studies and from Cre-lox mediated gene deletion experiments which have highlighted the importance of non-neuronal cells in the disease progression. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Recently, the generation of new animal models of ALS has been made possible with the discovery of ALS-linked mutations in other genes encoding for alsin, dynactin, senataxin, VAPB, TDP-43 and FUS. Following the discovery of mutations in the TARDBP gene linked to ALS, there have been some reports of transgenic mice with high level overexpression of WT or mutant forms of TDP-43 under strong gene promoters. However, these TDP-43 transgenic mice do not exhibit all pathological features the human ALS disease. Here, we will describe these new TDP-43 transgenic mice and discuss their validity as animal models of human ALS.