Mutations in the enzyme Cu/Zn superoxide dismutase (SOD) have been linked to about 20 percent of familial cases of amyotrophic lateral sclerosis (ALS), but there is no explanation yet for how the mutations contribute to ALS pathology. An extensive investigation of purified SOD in vitro, published in the June 3 PNAS Early Edition, suggests that the mutations interfere with protein folding.

There are a number of theories of how SOD mutations could lead to the death of motor neurons, including increased oxidative damage (see related news story) and disruption of axonal transport (see ARF related news story). There is also the matter of the abnormal SOD aggregates-these are found in neurons and glia in the familial, but not the sporadic cases-suggesting to some researchers that familial ALS might be a protein conformational disorder (e.g., prion disease), in which misfolded proteins form potentially toxic aggregates (see ARF related news story).

In all, more than 90 SOD mutations have been correlated with ALS, and many have been introduced to mice, where they produce abnormal SOD aggregates prior to the appearance of other cellular pathology characteristic of ALS in humans. Among the theories put forward to explain this effect of the mutations is that they interfere with proper folding of SOD.

Relatively little is known about the intrinsic properties of SOD protein, and Meiering and colleagues have undertaken to study the effects of disease-causing mutations in purified SOD in vitro. They chose four mutations that are quite different-e.g., several of the mutations alter the protein's structural flexibility, potentially affecting its conformation; another mutation introduces a hydrophobic region that has the potential to affect SOD dimerization.

In the current paper, Meiering and colleagues report that all four mutations lead to comparable decreases in the thermal stability of the protein and increases in the rate of experimentally (guanidinium Cl) induced unfolding. These results support the idea that SOD mutations of several types tip the balance in favor of unfolded or improperly folded forms of the protein that are more likely to aggregate. More support for this notion came from experiments in which aggregation was induced by trifluoroethanol (TFE) or by heat. Whereas wild-type SOD is highly stable and not easy to induce into aggregates, the SOD mutations led to aggregates under both manipulations. The morphologic characteristics of these aggregates were very similar to those seen in familial ALS patients and transgenic models. The process apparently involves a transition from small amorphous species to fibrils.

"Our data suggest that the different specific effects of SOD mutations may all lead to a common first step in [familial] ALS disease, namely, the aggregation of mutant SOD. SOD aggregation may increase because the mutant proteins have decreased stability, increased unfolding rate, and/or decreased folding rate...." conclude the authors.—Hakon Heimer

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  1. The concept of mutated SOD1 aggregate formation was previously evoked, but this article gives experimental evidence supporting this hypothesis. It remains now to explain why not all motoneurons (i.e. oculomotor nucleus) are not impaired.

References

News Citations

  1. Disputing the Dismuting—What Is the Real Role of SOD in ALS?
  2. Dynamitin in Motor Neurons: Dynamite for ALS Research?
  3. ALS—Could Stability Rather than Activity of SOD Hold the Key?

Further Reading

No Available Further Reading

Primary Papers

  1. . Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7021-6. PubMed.