Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase

Han Xiang Deng, Afif Hentati, John A. Tainer, Zafar Iqbal, Annarueber Cayabyab, Wu Yen Hung, Elizabeth D. Getzoff, Ping Hu, Brian Herzfeldt, Raymond P. Roos, Carolyn Warner, Gang Deng, Edwin Soriano, Celestine Smyth, Hans E. Parge, Aftab Ahmed, Allen D. Roses, Robert A. Hallewell, Margaret A. Pericak-Vance, Teepu Siddique

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Abstract

Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the SOD1 coding region revealed that the mutation Ala4 to Val in exon 1 was the most frequent one; mutations were identified in exons 2, 4, and 5 but not in the active site region formed by exon 3. The 2.4 Å crystal structure of human SOD, along with two other SOD structures, established that all 12 observed FALS mutant sites alter conserved interactions critical to the β-barrel fold and dimer contact, rather than catalysis. Red cells from heterozygotes had less than 50 percent normal SOD activity, consistent with a structurally defective SOD dimer. Thus, defective SOD is linked to motor neuron death and carries implications for understanding and possible treatment of FALS.

Original languageEnglish (US)
Pages (from-to)1047-1051
Number of pages5
JournalScience
Volume261
Issue number5124
DOIs
StatePublished - Jan 1 1993

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Cite this

Deng, H. X., Hentati, A., Tainer, J. A., Iqbal, Z., Cayabyab, A., Hung, W. Y., Getzoff, E. D., Hu, P., Herzfeldt, B., Roos, R. P., Warner, C., Deng, G., Soriano, E., Smyth, C., Parge, H. E., Ahmed, A., Roses, A. D., Hallewell, R. A., Pericak-Vance, M. A., & Siddique, T. (1993). Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science, 261(5124), 1047-1051. https://doi.org/10.1126/science.8351519