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Prions Rapidly 'Remodel' Good Protein Into Bad, Brown Study Shows

September 8, 2005
Brown University
Brown Medical School researchers have discovered that prions -- the culprits behind fatal brain diseases such as mad cow and its human counterparts -- convert healthy protein into abnormal protein through an ultrafast process similar to DNA replication. The breakthrough finding, published in Nature, helps explain how prions multiply and lead to illness.

PROVIDENCE, R.I. — Two Brown Medical School biologists havefigured out the fate of healthy protein when it comes in contact withthe infectious prion form in yeast: The protein converts to the prionform, rendering it infectious. In an instant, good protein goes bad.

Thisquick-change “mating” maneuver sheds important light on the mysteriousmolecular machinery behind prions, infectious proteins that cause fatalbrain ailments such as mad cow disease and scrapie in animals and, inrare cases, Creutzfeldt-Jacob disease and kuru in humans.

Becausesimilar protein self-replication occurs in neurodegenerative diseases,the findings, published in the latest issue of Nature, may also helpexplain the progression of Alzheimer’s, Parkinson’s and Huntington’sdiseases.

Graduate student Prasanna Satpute-Krishnan andAssistant Professor Tricia Serio, both in Brown’s Department ofMolecular Biology, Cell Biology and Biochemistry, conducted theresearch using Sup35, a yeast protein similar to the human prionprotein PrP.

The researchers tagged a non-prion form of Sup35with green fluorescent protein in one group of cells and “mated” thesecells with another group that contained the prion form. When the twoforms came in contact in the same cell, the green-glowing, healthyprotein changed pattern – a visual sign that it converted to the prionform. These results were confirmed in a series of experiments usingdifferent biochemical and genetic techniques.

Because proteinscan’t replicate like DNA and RNA – the genetic material in bacteria,viruses and other infectious agents – the research helps explain thepuzzling process of how prions multiply and spread infection.

Satpute-Krishnansaid the speed of protein conversion was surprising. “The prions weretaking all the existing protein and refolding it immediately,” shesaid. “It’s a very, very rapid change.”

After the conversion, theyeast cells remained healthy but had new characteristics. This survivalsupports the theory that prions have endured through evolution becauseshape-shifting is advantageous, allowing cells to avoid stress byrapidly adjusting to a new environment.

“Our studies provide someinsight into how the appearance of a misfolded protein – a rare event –can lead to devastating neurological diseases,” said Serio. “Just asmall amount of prion-state protein can rapidly convert healthy proteininto a pathogenic form.”

The National Cancer Institute and the Pew Scholars Program in the Biomedical Sciences funded the research.

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Materials provided by Brown University. Note: Content may be edited for style and length.

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Brown University. "Prions Rapidly 'Remodel' Good Protein Into Bad, Brown Study Shows." ScienceDaily. ScienceDaily, 8 September 2005. <>.
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