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Review
. 2003 Apr 1;100(7):3617-22.
doi: 10.1073/pnas.0730423100. Epub 2003 Mar 24.

Misfolded CuZnSOD and amyotrophic lateral sclerosis

Joan Selverstone Valentine  1 , P John Hart
Affiliations
Review

Misfolded CuZnSOD and amyotrophic lateral sclerosis

Joan Selverstone Valentine et al. Proc Natl Acad Sci U S A. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5-10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper-zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.

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Figures

Figure 1
Figure 1
Structure of a monomer of wild-type-like pathogenic SOD1 mutant G37R [PDB ID code 1AZV (69)]. The positions of the G37R and A4V mutations are indicated with red spheres. The copper and zinc ions are represented by blue and magenta spheres, respectively. The wild-type-like mutations (most of which are not shown) are found scattered throughout the β-barrel of the protein, shown in gold. The electrostatic loop is cyan and the zinc loop and metal-binding ligands are shown in black. The positions of the metal-binding-region mutations are represented by yellow spheres. The position of Cys-111 is represented by a green sphere. Asp-124, a residue termed the “secondary bridge,” links the electrostatic and zinc loops and the copper- and zinc-binding sites. The second subunit of the G37R homodimer is generated by a rotation of 180° around the axis indicated.
Figure 2
Figure 2
Structure of a monomer of wild-type-like pathogenic SOD1 mutant G37R, rotated 180° relative to the view shown in Fig. 1. The electrostatic loop is shown in cyan and the zinc loop is shown in black. β-Strands 5 and 6, the edge strands of the SOD1 β-sandwich (see text), are shown in red. The zinc loop projects out of the plane of the paper toward the viewer such that when two SOD1 proteins encounter each other in solution, they are sterically hindered from participating in protein–protein interactions at the edge strands. This edge strand protection could be lost if the zinc loop loses its wild-type conformation or becomes mobile because of mutation, metal deficiency, or both. The second subunit of the G37R homodimer is generated by a 180° rotation around the axis indicated.
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