ALS MND superoxide dismutase SOD1 fALS

Twenty years ago today, a team of more than 30 scientists at 13 research hospitals and universities reported the first gene, superoxide dismutase 1 (SOD1), linked to ALS. The gene encodes an enzyme critical to detoxify free radicals that are created during breathing. 

Scientists now estimate that mutations in the SOD1 gene explain about 1 in 5 cases of the inherited form of the disease.  The landmark discovery led to the identification of key players in ALS. And, paved the way toward preclinical testing of potential treatments and the first genetic test for the disease.  Take a look back at these advances by exploring our timeline.  Click on the text to learn more.

Image credits: Mark Dumont, Nature Publishing Group, NIGMS, Rockefeller University Press and George Shuklin.


Rosen, D.R. et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415), 59-62.  Abstract  |  Full Text  (Subscription Required)

Bowling, A.C., Schulz, J.B., Brown, R.H. Jr and Beal, M.F.  (1993)  Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis.  Journal of Neurochemistry 61(6), 2322-2325. Abstract  |  Full Text  (Subscription Required)

Gurney, M.E. et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.  Science 264(5166), 1772-1775. Abstract  |  Full Text  (Subscription Required)

Gurney, M.E., Cutting, F.B., Zhai, P., Doble, A., Taylor, C.P., Andrus, P.K. and Hall, E.D. (1996) Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Annals of Neurology 39(2), 147-157. Abstract  |  Full Text  (Subscription Required)

Bruijn, L.I., Houseweart, M.K., Kato, S., Anderson, K.L., Anderson, S.D., Ohama, E., Reaume , A.G., Scott, R.W. and Cleveland, D.W. (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.  Science 281(5384), 1851-1854.nbsp; Abstract  |  Full Text  (Subscription Required)

Tobisawa, S., Hozumi, Y., Arawaka, S., Koyama, S., Wada, M., Nagai, M., Aoki, M., Itoyama, Y., Goto, K. and Kato T. (2003) Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice. Biochemical and Biophysical Research Communications 303(2), 496-503.  Abstract  |  Full Text  (Subscription Required)

Clement, A.M. et al. (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642), 113-117.  Abstract  |  Full Text  (Subscription Required)

Turner, B.J., Atkin, J.D., Farg, M.A,. Zang, D.W., Rembach, A., Lopes, E.C., Patch, J.D., Hill, A.F. and Cheema SS. (2005) Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis.  Journal of Neuroscience 25(1), 108-117.  Abstract  |  Full Text  

Boillée, S., Yamanaka, K., Lobsiger, C.S., Copeland, N.G., Jenkins, N.A., Kassiotis, G., Kollias, G. and Cleveland, D.W. (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778), 1389-92. Abstract  |  Full Text  (Subscription Required)

Scott, S. et al. (2008) Design, power, and interpretation of studies in the standard murine model of ALS.  Amyotrophic Lateral Sclerosis 9(1), 4-15.  Abstract  |  Full Text  (Subscription Required)

Yamanaka, K., Chun, S.J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D.H., Takahashi, R., Misawa, H. and Cleveland, D.W. (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neuroscience 11(3), 251-253.  Abstract  |  Full Text

Münch, C., O'Brien, J. and Bertolotti, A. (2011) Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells.  Proceedings of the National Academy of Sciences 108(9), 3548-3553.  Abstract  |  Full Text  

Igoudjil, A., Magrané, J., Fischer, L.R., Kim, H.J., Hervias, I., Dumont, M., Cortez, C., Glass, J.D., Starkov, A.A. and Manfredi, G. (2011)  In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space. Journal of Neuroscience 31(44), 15826-15837. Abstract  |  Full Text  

van Blitterswijk, M. et al. (2011) Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis.Amyotrophic lateral sclerosis 12(6):430-438. Abstract  |  Full Text