Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig'sdisease after its famous victim, is a fatal neurodegenerative disorder.ALS, which strikes most often during middle age, targets motorneurons. It begins as motor weakness in the limbs and progresses toparalysis, then death.

In the majority of ALS sufferers, the disease is not easily attributableto inheritance. However, a portion of affected individuals do acquirethe disease genetically. In these familial cases, ALS inheritanceappears to be a dominant mutation that is not sex-linked, but ispresent on an autosomal chromosome. A further subset of theseindividuals have a mutation in the copper/zinc superoxide dismutase(SOD-1) gene that reduces the activity of this enzyme. SOD-1protects cells from the toxic effects of free radicals that can interactwith and oxidize biomolecules and cellular structures.

This lessened SOD-1 activity in ALS patients implies a causalrelationship between it and the motor neuron degeneration thatmarks the disease.

A paper in the current Proceedings of the National Academy ofSciences (PNAS) dated Jan. 31, confirms SOD-1's involvement inALS. Its title: "Transgenic mice expressing an altered murinesuperoxide dismutase gene provide an animal model of amyotrophiclateral sclerosis."

Its senior author, neuroscientist Jon Gordon, and his colleagues at theMt. Sinai School of Medicine, of New York, constructed a mouseSOD-1 gene with the missense mutation seen in humans and insertedit into a mouse genome, to create a transgenic murine ALS model. Ina new twist, the mutant SOD-1 appears to have its effect on theprogression of ALS by gaining a toxic function, not by a reduction inactivity.

The team's altered mouse SOD-1 gene has a missense mutation in itsfourth exon that replaces the glycine at amino acid residue 86 withan arginine. The mutated gene's expression in the central nervoussystem triggered a rapidly progressive, age-related decline in motorneuron function. As the PNAS paper reported, "all affected animalswere normal at the age of three months but dead by four months, andthe disorder progressed from a mild gait abnormality to totalparalysis within a five-day period in all cases."

Gordon and his co-authors deemed most interesting their finding thatSOD-1 activity in the transgenic mouse tissues was normal.Apparently, the background of expression by the normalcomplement of SOD-1 genes was enough to maintain normalactivity. This led the investigators to conclude that the mutanttransgene must have an altered function, as yet unidentified, thatcauses the neural degeneration.

Gordon explained to BioWorld Today: "The effect seems to be dueto the mutant enzyme generating a product in vivo that has a toxiceffect, rather than the mouse losing its ability to deal with oxidationby free radicals."

To bolster this conclusion, the investigators introduced an extra copyof the normal SOD-1 gene into more than 100 transgenic mice. AsPNAS reported, after more than six months of observation, theseanimals remained free of ALS-like abnormalities. Thus, Gordon said,the previous hypothesis that the reduced SOD-1 activity observed infamilial ALS patients leads to this neurodegenerative syndrome maynot be correct.

Transgenic Mice Test ALS Therapeutics

ALS sufferers are symptom-free until the onset of their disease, thendegeneration occurs quickly, leading to death. But because their ageat onset is not uniform, clinicians have questioned whether thedisease might actually be progressive instead of precipitous.

Newer work from Gordon's laboratory at Mt. Sinai sheds light onthis issue. "We have looked at apparently healthy younger transgenicmice and found that they do have measurable neural degeneration.This leads us to believe that the disease is slowly progressive inhumans, and that environmental effects eventually cause it tomanifest itself."

Gordon observed that the major advantage of this transgenic mousesystem is the ability it affords to study a homogeneous populationthat has a uniform response. "With this model available," he said,"the variable course of the disease seen in humans no longer presentsa problem for therapeutic testing. The consistency of onset timing,and effects seen in these mice, will allow therapeutic evaluation anddiagnostic test development to be done in a rigorous fashion."

While this model system may be strictly applicable to only a subsetof ALS patients, Gordon said that the insights gained fromunderstanding SOD-l's role in them would be applicable to otherALS sufferers. n

-- Chester Bisbee Special To BioWorld Today

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