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Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site

  1. Author:
    Wang, J.
    Xu, G. L.
    Gonzales, V.
    Coonfield, M.
    Fromholt, D.
    Copeland, N. G.
    Jenkins, N. A.
    Borchelt, D. R.

  2. Author Address

    Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA Borchelt DR Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
    1. Year: 2002
  2. Journal: Neurobiology of Disease
    1. 10
    2. 2
    3. Pages: 128-138
  4. Type of Article: Article
  1. Abstract:

    Mutations in Cu/Zn superoxide dismutase 1 (SOD1) have been linked to dominantly inherited forms of amyotrophic lateral sclerosis (FALS). To test the hypothesis that the toxicity of mutant SOD1 originates in Cu2+-mediated formation of toxic radicals, we generated transgenic mice that express human SOD1 that encodes disease-linked mutations at two of the four histidine residues that are crucial for the coordinated binding of copper (H46R/H48Q). We demonstrate that mice expressing this mutant, which possesses little or no superoxide scavenging activity, develop motor neuron disease. Hence, mutations in SOD1 that disrupt the copper-binding site do not eliminate toxicity. We note that the pathology of the H46R/H48Q mice is dominated by fibrillar (Thioflavin-S-positive) inclusions and that similar inclusions were evident in mouse models that express the G37R, G85R, and G93A variants of human SOD1. Overall, our data are consistent with the hypothesis that the aberrant folding/aggregation of mutant SOD1 is a prominent feature in the pathogenesis of motor neuron disease. (C) 2002 Elsevier Science (USA).

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