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Misshapen Proteins Tied to Various Diseases

Changes in structure, not chemistry, cause problems

FRIDAY, April 12, 2002 (HealthDayNews) -- Illnesses from Alzheimer's disease, Type II diabetes and Creutzfeldt-Jakob disease may be the result of protein folding gone awry.

Two new studies in the journal Nature report that misfolded proteins that clump together are harmful because of their abnormal shape, not because their chemistry has become toxic.

The findings suggest future therapies designed to prevent or target the misfolded proteins may help treat seemingly unrelated diseases. Christopher M. Dobson, a professor of chemistry and structural biology at the University of Cambridge in England, was a co-investigator on the first study.

Proteins need to collapse into one another to determine what their ultimate function will be.

For the last decade, Dobson's research has focused on how proteins go from their disordered state after they are first made inside a cell into their folded, functional state.

"As we were very much involved in understanding the folding process, we were able to focus on a different angle, which is what makes the protein misfold," he says.

Dobson says the deposits that form in the 20 or so protein misfolding conditions -- including Alzheimer's disease, the prion diseases (such as Creutzfeldt-Jakob disease), and even Type II diabetes -- are made up of thread-like structures.

However, he found that aside from the proteins linked to those diseases, other proteins in the laboratory could be "persuaded" to take these thread-like forms.

"We could form these thread-like structures in the test tube from virtually any protein that we wanted to if we got it under the right conditions," Dobson says. Moreover, "if you take any protein and misfold it into these aggregates [an abnormal collection of proteins], they will be damaging to the cells."

He explains this misfolding appears to happen when the normal process of protein folding goes awry, and the protein bonds incorrectly to itself. Dobson suspects that when this happens, "sticky" parts of the early aggregate protein that are normally hidden inside the properly folded protein are exposed, interfering with other parts of the cell.

As the more mature protein threads form, says Dobson, "a lot of the sticky regions of the protein get covered up and you end up with a rather innocuous type of material."

Other proteins called "molecular chaperones" normally protect folding proteins and destroy those that have misfolded. Dobson suspects that since most of the misfolding-related diseases are linked to aging, perhaps these cellular housekeeping functions become less efficient with time.

"We tend to accumulate these aggregates under some circumstances," he says. "Once these aggregates start to form, they actually seed the formation of other aggregates, and one can end up with large quantities of them."

He says that understanding the fundamental structural mechanisms of this misfolding may lead to new therapies for illnesses like Alzheimer's disease. In particular, he says, "if one wants an effective therapy, one should either try and stop the aggregates forming at all … or else try and get rid of these early aggregates."

The second study, led by Dr. Dennis J. Selkoe of the Center for Neurologic Diseases at Harvard Medical School and Brigham and Women's Hospital in Boston, focused on the protein linked to Alzheimer's disease.

"There's been rapidly growing evidence that the amyloid-beta protein is at the root of Alzheimer's disease," says Selkoe. "But a missing link in the story was exactly what form of amyloid-beta causes trouble, and whether it directly causes trouble."

That's where Selkoe's new study comes into the picture. The researchers discovered that a certain type of amyloid-beta protein, which they called oligomers -- doublets, triplets and quadruplets of the protein -- are to blame.

The researchers took about one-millionth of a liter of the medium that surrounds cells that make natural oligomers of amyloid-beta and injected it into the brains of laboratory rats.

"When you micro-inject just those forms into a living, anesthetized rat, you dramatically interfere with its memory circuits," Selkoe says. The process severely impaired the rats' ability to lay down new memories.

The researchers also treated the cultured cells with a chemical called gamma-secretase, which blocks an enzyme that makes amyloid-beta protein. Selkoe and his colleagues used just enough to lower the level of monomers, the single-unit amyloid-beta proteins, by about 40 percent.

"That led to a 90 percent drop in the oligomers," he says. "That's because the oligomers are made from the monomers."

"It very precisely defines biochemically who the bad guy is and how little is needed to cause trouble, and what the trouble is that interferes with the mechanism of memory function," he says.

"This provides a missing link in the amyloid hypothesis of Alzheimer's," says Selkoe. "It puts the smoking gun in the hands of a certain form." At the same time, he says, it may apply to other diseases, such as Parkinson's disease and Huntington disease, both of which involved the formation of oligomers.

Selkoe says this paper points researchers in the direction of potential therapies that would lower the level of a specific form of amyloid-beta.

Lary C. Walker, director of the Alzheimer's Disease Program at Pfizer Ann Arbor Laboratories in Ann Arbor, Mich., agrees that therapies that would prevent the change in structure would have an effect, but cautions that such treatments are "quite a ways down the road."

"This is an entirely new way of thinking about what causes a whole variety of diseases of old age," Walker says. "The good news is that people are thinking in this way, and this is going to lead to -- more or less -- a revolution in the way we think about these [proteins] and a revolution in the way we think about treating the diseases."

Walker says that scientists are now on the threshold of new discoveries. "Hopefully … we'll be able to use what we learn to treat a variety of diseases that have always been thought of as being completely unrelated."

What To Do

You can read a simple explanation of protein folding from the Federation of American Societies for Experimental Biology, or check out this article on protein folding from Scientific American.

For information on Alzheimer's, go to the Alzheimer's Association.

SOURCES: Christopher M. Dobson, Ph.D., professor, Departments of Chemistry and Structural Biology, University of Cambridge, Cambridge, England; Dennis J. Selkoe, M.D., professor, neurologic diseases, Harvard Medical School, Brigham and Women's Hospital, Boston; Lary C. Walker, Ph.D., director, Alzheimer's Disease Program, Pfizer Ann Arbor Laboratories, Ann Arbor, Mich.; April 4, 2002, Nature
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