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

DOI Web Site 被引用文献55件
  • Han-Xiang Deng
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Afif Hentati
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • John A. Tainer
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
  • Zafar Iqbal
    Department of Neurology, Northwestern University Medical School, Chicago, and Northwestern University Institute of Neuroscience, Chicago, IL 60611.
  • Annarueber Cayabyab
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Wu-Yen Hung
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Elizabeth D. Getzoff
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
  • Ping Hu
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Brian Herzfeldt
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Raymond P. Roos
    Department of Neurology, University of Chicago, Chicago, IL 60637.
  • Carolyn Warner
    Department of Neurology, Dent Neurological Institute, Buffalo, NY 14209.
  • Gang Deng
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Edwin Soriano
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Celestine Smyth
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Hans E. Parge
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
  • Aftab Ahmed
    Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.
  • Allen D. Roses
    Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710.
  • Robert A. Hallewell
    Department of Biochemistry, Imperial College, London SW7 2AZ, U.K.
  • Margaret A. Pericak-Vance
    Department of Medicine (Neurology), Duke University Medical Center, Durham, NC 27710.
  • Teepu Siddique
    Departments of Neurology and of Cell, Molecular, and Structural Biology, Northwestern University Medical School, Chicago, IL 6061 1, and Northwestern University Institute of Neuroscience.

抄録

<jats:p> Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene ( <jats:italic>SOD1</jats:italic> ) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the <jats:italic>SOD1</jats:italic> coding region revealed that the mutation Ala <jats:sup>4</jats:sup> 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. </jats:p>

収録刊行物

  • Science

    Science 261 (5124), 1047-1051, 1993-08-20

    American Association for the Advancement of Science (AAAS)

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