Ill-shaped proteins clue to Alzheimer's

New research suggests 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 today'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.

Major advance

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 roles they play are dictated by both their makeup and the three-dimensional shape they take on when folded.

On occasion, folding can go awry. Accumulations of these rogue proteins are common in what researchers categorize as protein deposition diseases.

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 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, in laboratory rats, 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 Dennis Selkoe, a neurologist at Harvard Medical School and Brigham and Women's Hospital in Boston.