By David N. Leff

If Mother Nature patented her inventions, human beings would be spending all their time fighting infringement lawsuits.

Take the wheel, mankind's first mechanical device. Rotifera got there first, with their rear-engine rotors of beating cilia that propel these minute aquatic organisms through the water.

Airplane wings? Birds and bats perfected that aerodynamic structure long before wind tunnels and computers designed them.

Dam building? Beavers showed the way.

Textile spinning and weaving? Spiders pioneered that.

Chemical warfare? Snakes and toadstools were way ahead.

Balloons? Look at the puffer fish.

The list of nature's intellectual properties goes on and on. It even foreshadowed one of humanity's most egregious sins against the natural environment — spreading the blight of hazardous wastes.

Where to bury spent nuclear fuel? How to clean up the epidemic of oil spills — from the Exxon Valdez and Kuwait's Iraqi-ignited wells to the innumerable industrial sites of mine tailings to leaking gasoline stations?

Here too, man-made industrial detritus has been anticipated by the toxic waste dumps of the human genome.

These cause the inherited storage diseases, in which the cells of the body pile up redundant proteins or lipids, but lack the enzymes to get rid of the toxic debris. Well-known examples include Gaucher's disease and adenosine deaminase deficiency (ADA). Then there are the triplet-codon neurodegenerative diseases.

Huntington's disease (HD), for one, is marked by the uncontrolled accumulation of mutant proteins in its sufferers' neurons, generated by repeating stretches of three base pairs in their chromosomes.

So is spinocerebellar ataxia (SCA) , which is among the commonest forms of inherited ataxia.

"SCA type 1 occurs worldwide in roughly one to four live births per 100,000," said neurologist and molecular geneticist Huda Zoghbi, at Baylor College of Medicine, in Houston. "It may be lower in the U.S.," she added, "is very rare in Japan, and quite common in parts of France, Italy and Northern Europe."

Unraveling How Triplets Do What Triplets Do

In a patient with the stumbling, staggering gait and other physical symptoms of ataxia, Zoghbi explained, the only way for a neurologist to distinguish SCA type 1 from other forms of the disease is by molecular testing. "This detects the triplet CAG [cytosine-adenine-guanine] expansion," she explained. "Such testing amplifies a portion of the mutant gene that contains the trinucleotide repeats. In SCA1 patients, the CAG number is typically larger than 40 iterations, while in normal individuals it's less than 40."

As in the CAG-repeating disease HD, when the malady is passed from generation to generation, the number of triplet codons expands, and the symptoms become more severe.

The average SCA1 patient's onset is diagnosed in mid-adulthood — the 30s or 40s. "Such patients whose onset is detected only in the 50s," Zoghbi continued, "will have deterioration of brainstem functions in their 50s, and die. Diagnosis in childhood is uncommon, but the disease progresses more rapidly, with death between five and ten years from onset."

Unlike most neurodegenerative diseases, SCA1 inflicts no mental disability, only physical devastation.

As in HD, SCA1's CAG encodes the amino acid glutamine. Long chains of this molecule, the Baylor team has found, are a major component of the toxic waste that resists disposal and accumulates in degenerating neurons.

Zoghbi is senior author of a paper in the June 1998 issue of Nature Genetics titled: "Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1."

In healthy people, the constant output of proteins is continuously removed by a waste-disposal system known as the ubiquitin-proteasome cascade. Ubiquitins are small polypeptides that go around tagging proteins earmarked for breakdown and recycling.

Proteasomes Break Up The Trash

This trash-removal proteolysis is then carried out by a massive complex of proteins called proteasomes.

"Because ubiquitin marks the proteins that are destined to enter the proteolysis pathway," Zoghbi told BioWorld Today, "we set out to investigate whether the proteolysis machinery — the proteasome — is altered in SCA1 patients. We found that indeed its distribution within neurons is altered, as it's clearly going to the site of these large protein aggregates.

Zoghbi went on to describe her proposed mechanism at work:

"You've got the glutamine protein. In its normal situation, it's got, say, 30 CAG triplets. When mutated, it might have 40 or 50 or more. And when it's mutated, the whole protein now aggregates.

"Since we knew that proteins are degraded in the proteosome, we wanted to see if the proteasome was altered. And the answer is yes. It doesn't localize normally. It gets redistributed to where these insoluble aggregates are building up in the nuclei of the neurons.

"So that suggested to us that the proteasome is very busy, trying desperately to get rid of these glutamine aggregates in neurons. Or else it's stuck there, being choked by the aggregates. We don't know what's happening," she observed.

"What we believe is happening is that the mutant protein with this longer triplet somehow is not being folded properly, and that's why it can't be degraded."

In their experiment, Zoghbi and her team used antibodies to identify components of the proteasome, and other proteins in the glutted neurons.

"That was the first half of our experiment," she recounted. "The second half was to investigate proteins known as chaperones. These help other proteins fold properly, and/or maintain them in a conformation that can be degraded by the proteasomes. Because the two phenomena, folding and degradation, are tied together, we wanted to see if the chaperones are altered as well."

Such was the case, they found, for one particular chaperone, named HDJ-2/HSDJ.

"We need to think of these proteins with expanded glutamines," she suggested, "which have an altered conformation, and possibly a misfolding problem, as somehow disrupting normal physiological proteolysis in the cell."

Zoghbi and her group are now making transgenic mice that express that chaperone, to cross-breed with SCA1 transgenics. "We will try to overexpress this chaperone," she said, "and see if that can help maintain the folding properties of mutant SCA1 protein, such that it can be handled by the proteasomes.

"To translate these things from an observation to a medical and therapeutic situation," she concluded, "is a very long road.

"But at least if we prove that this is a problem of misfolding, and if we can really show that it has to do with destruction of the proteolytic machinery in the cell, then one can possibly start screening for chemicals that either enhance chaperone activities or keep proteasomes more successful and active in the presence of these mutant proteins." *