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Mutant prions help cells foil harmful protein misfolding
Date:3/20/2011

PROVIDENCE, R.I. [Brown University] Romping clumps of misfolded proteins are prime suspects in many neurological disorders including Alzheimer's, Parkinson's, and Creutzfeld-Jakob Disease. Those diseases are devastating and incurable, but a team of biologists at Brown University reports that cells can fix the problems themselves with only a little bit of help. The insight suggests that there are more opportunities to develop a therapy for protein misfolding than scientists had thought.

"There are multiple steps that you could target," said Susanne DiSalvo, a Brown biology graduate student and lead author of a paper published in advance online March 20 in Nature Structural and Molecular Biology.

In the study, the research team, led by Tricia Serio, associate professor of medical science, explains how two different beneficial mutant prions managed to foil the amplification of harmful clumps of misfolded proteins in yeast. Cells have an internal quality assurance system to break up and refold misfolded proteins, but that system can be overwhelmed by diseases. DiSalvo was the first to observe that the mutants act at distinct stages to tip the balance back in favor of the cells, allowing them to overcome the problem.

Serio says the molecular mechanisms appear to explain how similar mutants solve protein misfolding in mammals, including people. The phenomenon had been poorly understood and has never been exploited to develop a successful therapy.

Misfolding is a vulnerable process

Until now most scientists guessed that the only way to stop the runaway misfolding was right at the beginning and assumed the mutants must be blocking that first step to keep the protein in a harmless form. DiSalvo's work instead suggests that there are many opportunities throughout the process where even a mild intervention could give cells what they need to gain the upper hand, Serio said.

"That's one of the biggest outc
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Contact: David Orenstein
david_orenstein@brown.edu
401-863-1862
Brown University
Source:Eurekalert

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