Misfolded proteins get self-help nudge
BROWN (US) — With a little assistance, cells are able to fix misfolded proteins—prime suspects in neurological diseases—on their own, a finding that could clear the way for the development of drug therapies.
A new study published in the journal Nature Structural and Molecular Biology shows how two different beneficial mutant prions are able to foil the amplification of harmful clumps of misfolded proteins in yeast.
“There are multiple steps that you could target,” says Susanne DiSalvo, a graduate student of biology at Brown University.
Cells have an internal quality assurance system to break up and refold misfolded proteins, but that system can be overwhelmed by diseases. The mutants act at distinct stages to tip the balance back in favor of the cells, allowing them to overcome the problem.
The molecular mechanisms appear to explain how similar mutants solve protein misfolding in mammals, including people. The phenomenon had previously been poorly understood and has never been exploited to develop a successful therapy.
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, says Tricia Serio, associate professor of medical science.
The new 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.
“That’s one of the biggest outcomes of Susanne’s work: that if you just even slightly interfere with this process, the cell can deal with it and get rid of it,” Serio says. “The dogma in the field is that these conformations were so abnormal the cell couldn’t resolve them.
“But what we’ve found is that this process of misfolding is so efficient the cells can’t keep up with it. If you make it even just a little bit less efficient the cell can get rid of the pathological state.”
One mutant prion, Q24R, hinders the ability of misfolded proteins to aggregate into harmful clumps like a dryer sheet that cuts down on static cling and makes it easier to fold laundry.
The other mutant prion, G58D, assists the cell by speeding up its ability to unfold and refold misfolded proteins like someone who helps untangle strings of holiday lights when they come out of storage.
The experiments show how mutants and cells work together. Cells would only be cured when a mutant was added and the cells’ own quality assurance system was allowed to work. Adding the mutant G58D, for example, could cure a cell of infection by the Sup35 prion, but if the cell’s quality assurance system was interrupted then it wouldn’t work.
The results show the importance of delving deeply into molecular networks, said Stefan Maas, who oversees Serio’s and other cellular signaling grants at the National Institutes of Health.
“These results are a great example of the power of system-level studies,” says Stefan Maas at the National Institutes of Health.
“By showing how two beneficial mutants cure the cell of prions, this study has revealed that small changes applied to distinct components of a molecular network can dramatically alter the outcome for the cell. These new insights may lead to new strategies for preventing or treating disorders that involve protein deposits.”
But those strategies may require turning proteins into pills. While beneficial mutant prions confer resistance to prion infection in nature, they haven’t been successful in reversing an established infection because sustained delivery into the body is too challenging.
But a small molecule drug mimic, if developed, could target infected tissues more effectively over a longer period to slow or perhaps even reverse disease progression.
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