Superoxide Dismutase
In 1993 Rosen and colleagues published a paper which identified mutations to the copper-zinc-superoxide dismutase 1 (SOD1) gene as being responsible for one form of MND, known as ALS, in certain families. Subsequent investigations of this gene have identified more than 100 different mutations in different individuals and families around the globe. It is estimated that only about two to three percent of all ALS cases are due to mutations to the SOD1 gene. Despite this low level of involvement (SOD1 is not implicated in at least 97% of ALS cases) much research activity has focused on the SOD1 gene, driven largely by the availability of strains of mice and rats with mutations induced in their SOD1 genes similar to mutations found in humans.
While it has always been hoped that research using animal models would give greater insight into the disease processes and quickly lead to drug treatments, so far this has not happened. Drugs which have given good results in animal tests have failed to translate to humans. A number of reasons have been proposed to explain this. The mice or rats of an experimental strain are highly inbred and all have the same mutation to their SOD1 gene. Therefore their response to an experimental drug treatment, such as minocycline, will be more uniform than the response of humans with ALS, 97 to 98 percent of whom will not have a SOD1 mutation at all.
Not all mutations to the SOD1 gene associated with ALS disrupt the function of the SOD1 enzyme in the same way. Some mutations have virtually no effect on the ability of the SOD1 enzyme to work effectively when compared to normal or “wild-type” SOD1. Some mutations affect the part of the enzyme where copper is held, others affect the part where zinc is held while yet other mutations affect neither of these areas. Yet each of these different kinds of mutation seems to be involved in ALS, leading to the suggestion that mutated SOD1 has gained a toxic function that wild type SOD1 does not have.
