SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments

• Published in: Mammalian genome 2011-08, Vol.22 (7-8), p.420-448
• Main Authors: Joyce, Peter I., Fratta, Pietro, Fisher, Elizabeth M. C., Acevedo-Arozena, Abraham
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - therapy; Animal Genetics and Genomics; Animal models; Animals; Axonal transport; Biomedical and Life Sciences; Caenorhabditis elegans; Cell Biology; Disease Models, Animal; DNA-binding protein; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Dogs; Drosophila; Excitotoxicity; Human Genetics; Humans; Inflammation; Life Sciences; Mice; Mitochondria; Motor neuron disease; Mutation; Neurotrophins; Protein folding; Rats; Regulatory sequences; RNA processing; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Zebrafish
• ISSN: 0938-8990; 1432-1777
• DOI: 10.1007/s00335-011-9339-1

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure. Breakthroughs in understanding ALS pathogenesis came with the discovery of dominant mutations in the superoxide dismutase 1 gene ( SOD1 ) and other genes, including the gene encoding transactivating response element DNA binding protein-43 (TDP-43). This has led to the creation of animal models to further our understanding of the disease and identify a number of ALS-causing mechanisms, including mitochondrial dysfunction, protein misfolding and aggregation, oxidative damage, neuronal excitotoxicity, non-cell autonomous effects and neuroinflammation, axonal transport defects, neurotrophin depletion, effects from extracellular mutant SOD1, and aberrant RNA processing. Here we summarise the SOD1 and TDP-43 animal models created to date, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic.