By David N. Leff

What in the world can Alzheimer's disease (AD) have in common with mad cow disease? One short answer might be prions; another, amyloid fibrils.

These two shifty molecules also wreak their horrors on Creutzfeldt-Jakob disease (CJD), plus a score of other related pathologies, including Type II diabetes and Parkinson's disease, not to mention aging. Another common denominator of these amyloidoses is the microscopic, threadlike fibrils they spawn in affected tissues all over the body, not just in the brain.

"I think if one took some of the non-brain diseases, such as diabetes Type II," observed chemical and structural biologist Christopher Dobson, at Oxford University in England, "probably what's happening there is simply the deposition of this fibrillar structure, which is enough to cause major damage to the organs in which it occurs. But in the brain diseases - Alzheimer's, Parkinson's, CJD - what seems to be the case is that the fibrils, or more probably the aggregates that eventually develop into these fibrils, are toxic to the neurons. So they actually cause cell death.

"And the senile neuritic plaques that you get in Alzheimer's, for example," Dobson continued, "may well be just the accumulation of these fibrillar structures as they assemble into larger units. Clearly, they're not doing any good in the brain, but it may well be that they're not really the cause of major problems. It may simply be that when proteins start aggregating, and begin the process of sticking together to get a structure that eventually forms the fibrils and then the plaques, it is these early stages that actually cause damage to the cells, and cause some of them to die."

Dobson is senior author of a brief communication in the journal Nature, dated March 8, 2001. Its bland title reads: "Amyloid fibrils from muscle myoglobin." But then its subtitle turns up the heat: "Even an ordinary globular protein can assume a rogue guise if conditions are right."

"Our idea," Dobson told BioWorld Today, "is that in these diseases the proteins are reverting to their most primordial structure. For example, in many of the familial diseases, there's a mutation in the protein sequence, which means that it doesn't fold up as tightly or cooperatively as the normal protein would. So it has a tendency to unfold and then convert into this fibrillar structure."

Aging - Prion Disease Risk Factor?

"Also, we think that as we grow old," Dobson continued, "the regulation of our cells may somewhat worsen, so other proteins become able to form these types of structures. And in the prion diseases - mad cow and CJD - some infectious agent, perhaps even just the crystal-like seeding process of adding fibrils or aggregates to cells, can increase the rate at which the prions undergo this transition. And this results in the transmissibility of those diseases."

Dobson explained why he and his group chose the muscle protein myoglobin to test their hypothesis. "We found that a number of proteins could convert into fibrous structures under mildly denaturing conditions of pH, temperature, buffer and so on - that is, becoming soluble. We chose the archetypal myoglobin because it's almost completely helical in its major structure. Its polypeptide chain is folded up into helices, but in the fibrils they're structural sheets.

"Myoglobulin," Dobson went on, "which supplies oxygen to the body's muscle cells, was the first protein to have its crystal structure determined. It has been studied by large numbers of people over a long length of time. Of course they've been looking only for the folded structure that's common in biology. There's a large amount of it in our bodies," he continued, "so we thought it was the ultimate test of this generic idea. That is, if by putting it under mildly denaturing conditions, and we did get disease-associated fibrils, then I think it would show that virtually any proteins could go into this. Indeed," he recounted, "our converted myoglobin proved undistinguishable from disease-related amyloid fibrils. So that's why I think Nature accepted it as a communication, because it surprised an awful lot of people that we could do this.

"If you start to get AD or some of the related diseases," Dobson went on, "they progress rapidly because their clinical course effectively speeds up the protein conversion process. And this may also be the origin of the prion diseases. We believe our evidence strongly supports the fact that proteins can in an unassisted way convert to these types of structures. But what we're saying is that the prion is not special in having this ability to go into these conformations. That is something very common.

"But what is special about the prion diseases," he pointed out, "is that they are transmissible - infectious. The likely origin of the spongiform encephalopathies in cows and people may be the seeding mechanism, or something much more complicated."

Dobson, who directs the Oxford Center for Molecular Sciences, is now focused on forestalling or slowing this unique disease process. "We're a long way from over-the-counter medicine at the moment," he allowed, "but our discovery does suggest new paths we can take in the search for cures. For example, there are compounds that might stabilize helical proteins, and prevent them from converting into their alternative prion structures. Or we could find out how to stop prions that have already formed from clumping together into plaques. Most exciting is the prospect that we could design more stable proteins, which could be administered to patients by gene therapy. Of course," he added, "this option is very much in the future."

From Therapeutic To Industrial Perspectives

But beyond therapy, Dobson is pursuing a quite different tangent - materials science and devices.

"One of the things we've become interested in," he recounted, "is the possibility that these types of proteins, although they're very damaging if deposited within our bodies, actually may be very interesting materials if we make them in the laboratory. So one of the things we have been doing is exploring the possibility of using these almost as incidentally functionizable nano-structures with interesting biocompatibility properties. They might actually have uses either in biotechnology or materials sciences."

"The university," he concluded, "already has some issued patents." n