Decidedly, oxygen plays good cop, bad cop in the humanbody.

Wearing its white hat, bearing the badge "O2," oxygen isliterally the gas of life. Under its black hat, labeled "O2-"the oxygen free radical, shy one electron, sows diseaseand death among susceptible cells. To wreak itsrampages, the rogue element connives with a hydrogenatom to form superoxide, HO2.

As life on earth evolved, aerobic cells developed ways ofdealing with superoxide. Their principal protector is anenzyme called superoxide dismutase, better known asSOD. This life-saving enzyme, by a unique process calleddismutation, catalyzes the further conversion of HO2 tohydrogen peroxide, H2O2.

SOD is a metal-binding enzyme that contains copper andzinc. The former, said molecular geneticist John Phillips,of Guelph University, Ontario, "is particularly notorious.In many, if not most, cell types," he told BioWorldToday, "the bulk of the copper in a cell stays bound toSOD. Therefore, if a mutation in the SOD gene alters thisbinding, you may end up with a copper toxicity problem."

Such a problem may well beset people afflicted with LouGehrig's disease _ amyotrophic lateral sclerosis (ALS),including its inherited familial form, FALS. Thisintractable, untreatable motor neuron disease begins withcreeping paralysis, and ends three to five years later ininevitable death. (See BioWorld Today, May 11, 1995, p.1.)

"Mutation in the SOD gene and in its peptide product,"Phillips suggests, "by itself could be sufficient to explainat least part of the symptomology in FALS."

How Do SOD Mutants Cripple FALS Nerves?

What makes the motor neuron in FALS patients"hypersusceptible to whatever it is that's being altered bythese mutations," Phillips continued, "is a big question."Two schools of research are at present reporting twoalternative, and possibly overlapping, interpretations thatseek to answer that question.

One persuasion, of which Phillips is a prime exponent,relates these hyper-reduced levels of SOD activity to thegenetic carriers of its many and varied mutations.Typically, the heterozygotic carrier of a mutant variantgene is protected from the effect of the mutation by his orher back-up parental variant.

Not so for carriers of missense SOD mutations. "Theseheterozygotes," Phillips said, "produce far less SODactivity than one would expect from a carrier. Some ofthem are down as low as around ten percent of normal,"despite having inherited a second, normal, gene.

Phillips' laboratory at Guelph deals with the moleculargenetic analysis of reactive oxygen metabolism. He andhis colleagues have studied these phenomena, particularlySOD mutation, in the archetype of fast-breedingeukaryotes, Drosophila melanogaster _ the fruit fly.

"Once it became known," Phillips observed, "that ourmissense mutations within the SOD gene were in factlinked to Lou Gehrig's disease in humans, it became clearthat all of the informative and experimental work we haddone on Drosophila for a number of years could have animportant bearing on the human FALS situation."

Phillips' latest findings appear in today's Proceedings ofthe National Academy of Sciences (PNAS). His reportbears the fully explanatory title: "Subunit-destabilizingmutations in Drosophila copper/zinc superoxidedismutase: Neuropathology and a mode of dimerdisequilibrium."

Earlier this year, the alternative school of SOD thoughthad published a paper in PNAS dated Jan. 31, titled"Transgenic mice expressing an altered murinesuperoxide dismutase gene provide an animal model ofamyotrophic lateral sclerosis." (See BioWorld Today,Feb. 7, 1995, p. 6.)

Their results, Phillips said, "in which they introduce amutant SOD gene into another otherwise wild-type (forSOD) mouse, with the animal then proceeding to displaysymptoms of neurodegenerative disease, are subject todifferent kinds of interpretations.

Oxygen Radical Rampage Or Gain Of Function?

"One of these," he continued, "favored by many of thetransgenic-mouse people, is that their experimentsdemonstrate that the FALS mutation is a `dominant gain-of-function mutation,' and that the mutant SODpolypeptide is conferring some sort of negative effect onthe cell that has nothing to do with oxygen-radicalmetabolism. So it's a sort of toxic peptide."

Phillips contrasts the two interpretations: "The mousepeople would suggest that the motor neuron is itselfuniquely susceptible to a kind of dominant gain offunction conferred by these mutations."

He added, "It could be, on the other hand, that the motorneuron has a particular physiology that makes very slightchanges in oxygen radical metabolism very deleterious tothat particular cell type. But dominant gain of functiondoes not necessarily rule out alterations in oxygen radicalmetabolism, which could still be the proximate cause ofcytotoxicity in these neurons."

Phillips' PNAS paper ends by suggesting that its report of"striking suppression of symptoms normally associatedwith SOD mutations in Drosophila should have importantetiological and therapeutic implications for FALS inhumans."

In his interview with BioWorld Today, he made the pointthat "You're not going to be able to use normal,recombinant SOD directly as a therapeutic agent, bywhatever mode of drug delivery or gene therapy, toovercome SOD mutations." He explained: "BecauseFALS patients will already have the mutant form, and, aswe have shown, and the transgenic mouse people haveshown, if you put a wild type and a mutant together,you're no better off.

"What you're really looking at," Phillips suggested, "is acopper toxicity problem. That should be the target, ratherthan trying to restore SOD function." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.