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Marred Proteins Linked to Diseases

April 08, 2002|ANDREW BRIDGES | ASSOCIATED PRESS

New research suggests that illnesses as diverse as Alzheimer's, Creutzfeldt-Jakob disease and adult-onset diabetes are caused by proteins that fold themselves into defective shapes, rather than proteins that have undergone harmful chemical changes.

As they develop, these aberrant protein forms can clump together and wreak molecular havoc on healthy cells, according to two studies in Thursday's issue of the journal Nature.

Previously, scientists believed that misfolding was an unusual occurrence limited to perhaps 20 or more protein types.

Instead, the effect may be common to any protein in the body, the researchers reported. Why it occurs remains unclear, but the process is believed to be associated with diseases that take decades to develop.

"There is lots of evidence that any protein can form these structures in principle," said Christopher Dobson of the University of Cambridge in England, who helped lead one of the studies.

Thomas Sudhof, a Dallas-based investigator with the Howard Hughes Medical Institute, called the paper a major advance because it demonstrates the particular stage at which the toxic effects of the misfolded proteins can be gauged.

Proteins are the agents of change and chemical messengers in cells, and they carry out the instructions encoded in genes. The specific roles they play are dictated by both their makeup and the three-dimensional shape they take on when folded.

In Creutzfeldt-Jakob disease--a degenerative brain disorder that resembles mad cow disease in its effects--a type of misfolded protein known as a prion may replicate itself and spread to other cells to cause progressive neurological damage. In diabetes, protein misfolding may be responsible for the blood-vessel damage, blindness and other debilitating effects of the disease.

In the Cambridge study, Dobson's team conducted a series of experiments in which they coaxed otherwise harmless muscle and bacteria proteins to take on misfolded, intermediate forms. Those forms proved toxic to healthy cells in laboratory cultures, he said.

In a separate study, scientists in Boston showed that the misfolded form of the amyloid beta protein disrupts the chemical mechanism in the brain by which memories are stored. Amyloid beta proteins are implicated in Alzheimer's. The study found that clusters of an intermediate form of amyloid beta were toxic to cells.

"It's not the big guys that are causing trouble or the little guys--it's the medium guys,'' said co-author Dennis Selkoe, a neurologist at Harvard Medical School and Brigham and Women's Hospital in Boston. He said tests showed that drugs can reduce the toxic accumulation of the intermediate form of amyloid beta in the brains of rats. But others cautioned the studies were too basic to be useful in developing new drugs.

"It's miles from any potential clinical intervention," said Bill Thies, vice president of medical and scientific affairs for the Chicago-based Alzheimer's Assn.

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