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Perspectives on the Mechanisms of Familial Amyotrophic Lateral Sclerosis Caused by Mutations in Superoxide Dismutase 1

  • David R. Borchelt
  • Philip C. Wong
  • Mark W. Becher
  • Lucie I. Bruijn
  • Don W. Cleveland
  • Neal G. Copeland
  • Valeria C. Culotta
  • Nancy A. Jenkins
  • Michael K. Lee
  • Carlos A. Pardo
  • Donald L. Price
  • Sangram S. Sisodia
  • Zhou-Shang Xu

Abstract

The mechanisms that lead to the selective degeneration of motor neurons in familial and sporadic amyotrophic lateral sclerosis (FALS and ALS) are not clearly understood. A subset of FALS cases are caused by mutations in Cu/Zn superoxide dismutase 1 (SOD1) (Deng et al., 1993; Rosen et al., 1993), but the mechanism by which mutant SOD1 injure motor neurons is unclear. We have suggested that abnormalities in Cu+ + metabolism may play a role in disease (Wong et al., 1995). This speculation derives from a number of observations: Cu++ can catalyze the formation of toxic radical species (Olanow, 1993; Brown, 1995); SOD1 is abundant in nervous tissues (Pardo et al., 1995; Tsuda et al., 1994); and the metal binding domains of the enzyme generally lack mutations (Brown, 1995; Wong and Borchelt, 1995). Moreover, several investigations have demonstrated that FALS-linked mutations do not necessarily compromise free radical scavenging activity (Borchelt et al., 1994; Fujii et al., 1995; Rabizadeh et al., 1995), and transgenic mice expressing mutant SOD1 develop motor neuron disease (MND) despite elevated or unchanged levels of superoxide scavenging activity (Gurney et al., 1994; Ripps et al., 1995; Wong et al., 1995). Although these data suggest that abnormal Cu++ metabolism could play a role in the disease, it is not clear whether mutations in SOD1 alter the levels of free Cu++ by diminishing the functions of an abundant Cu++-binding protein or whether mutations alter SOD1 structure to allow enzyme-bound Cu++ to catalyze deleterious reactions, such as protein nitration (Beck-man et al., 1993) or peroxidation (Stadtman, 1990; Yim et al., 1990; Stadtman and Oliver, 1991; Yim et al., 1993; Wiedau-Pazos et al., 1996).

Keywords

Superoxide Dismutase Amyotrophic Lateral Sclerosis Motor Neuron Amyotrophic Lateral Sclerosis Patient Motor Neuron Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • David R. Borchelt
    • 1
  • Philip C. Wong
    • 1
  • Mark W. Becher
    • 1
  • Lucie I. Bruijn
    • 2
  • Don W. Cleveland
    • 2
  • Neal G. Copeland
    • 3
  • Valeria C. Culotta
    • 4
  • Nancy A. Jenkins
    • 3
  • Michael K. Lee
    • 1
  • Carlos A. Pardo
    • 1
  • Donald L. Price
    • 5
  • Sangram S. Sisodia
    • 1
  • Zhou-Shang Xu
    • 2
  1. 1.Department of Pathology and the Neuropathology LaboratoryThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA
  2. 2.Department of Biological ChemistryThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA
  3. 3.Mammalian Genetics Laboratory, ABL-Basic Research ProgramNCI-Frederick Cancer Center Research and DevelopmentFrederickUSA
  4. 4.Departments of Biochemistry and Environmental Health SciencesThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA
  5. 5.Departments of Pathology, Neurology, and Neuroscience, and the Neuropathology LaboratoryThe Johns Hopkins University School of Medicine and School of Hygiene and Public HealthBaltimoreUSA

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