Amyotrophic Lateral Ssclerosis and Structural Defects in Cu,Zn Superoxide Dismutase

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 Ala 4 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.

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Affiliated Institutions

• Imperial College London GB
• Northwestern University US
• University of Chicago US
• Scripps Research Institute US
• Duke Medical Center US
• Dent Neurologic Institute US

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