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Size of Protein Aggregates, Not Abundance, Drives Spread of Prion-Based Disease

Mad Cow disease and its human variant Creutzfeldt -- Jakob disease, which are incurable and fatal, have been on a welcome hiatus from the news for years, but because mammals remain as vulnerable as ever to infectious diseases caused by enigmatic proteins called prions, scientists have taken no respite of their own. In the Oct. 29 edition of the journal Science, researchers at Brown University report a key new insight into how prion proteins -- the infectious agents -- become transmissible: In yeast at least, it is the size of prion complexes, not their number, that determines their efficiency in spreading.

"The dogma in the field was that the misfolding of the protein is sufficient to cause disease, and the clinical course of the infection depended on the amplification of the misfolded protein," said Tricia Serio, associate professor of molecular biology, cell biology and biochemistry. "But over the years in mammals it has become clear that the abundance of misfolded protein is not a good predictor of disease progression. The question is, What else has to happen for you to get the clinical pathology?"

Cells make prion proteins naturally, although biologists do not understand what their normal role is in mammals. When those proteins misfold in cells, they assemble into structures called aggregates, but other proteins, known as chaperones, attempt to break down the aggregates. The rates at which this assembly and disassembly occurs are determined by the shape or conformation that the prion protein has adopted.

"Different conformations of the same prion protein can dramatically alter the spread of pathology and the incubation time of prion diseases," Serio said. "We wanted to learn how."

By combining experiments in yeast cells with mathematical models, the Brown team found that what affects a prions' ability to transmit from cell to cell is the size of the structures into which they assemble, Serio said. If the aggregates become too large, they lose their transmissibility among cells. Prion aggregates that remain small are transmitted with greater efficiency.
 
 

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