Brown Team Finds Crucial Protein Role in Deadly Prion Spread
A single protein plays a major role in deadly prion diseases by smashing up clusters of these infectious proteins, creating the “seeds” that allow fatal brain illnesses to quickly spread, new Brown University research shows.
The findings are exciting, researchers say, because they might reveal a way to control the spread of prions through drug intervention. If a drug could be made that inhibits this fragmentation process, it could substantially slow the spread of prions, which cause mad cow disease and scrapie in animals and, in rare cases, Creutzfeldt-Jacob disease and kuru in humans.
Because similar protein replication occurs in Alzheimer’s and Parkinson’s diseases, such a drug could also slow progression of these diseases as well.
“The protein fragmentation we studied has a big impact on how fast prion diseases spread and may also play a role in the accumulation of toxic proteins in neurodegenerative diseases like Parkinson’s,” said Tricia Serio, an assistant professor in Brown’s Department of Molecular Biology, Cell Biology and Biochemistry and lead researcher on the project.
The findings from Serio and her team, which appear online in PLoS Biology, build on their groundbreaking work published in Nature in 2005. That research showed that prions – strange, self-replicating proteins that cause fatal brain diseases – convert healthy protein into abnormal protein through an ultrafast process.
This good-gone-bad conversion is one way that prions multiply and spread disease. But scientists believe that there is another crucial step in this propagation process – fragmentation of existing prion complexes. Once converted, the thinking goes, clusters of “bad” or infectious protein are smashed into smaller bits, a process that creates “seeds” so that prions multiply more quickly in the body. Hsp104, a molecule known to be required for prion replication, could function as this protein “crusher,” Serio thought.
To test these ideas, Serio and members of her lab studied Sup35, a yeast protein similar to the human prion protein PrP. They put Sup35 together with Hsp104, then activated and deactivated Hsp104. They found that the protein does, indeed, chop up Sup35 complexes – the first direct evidence that this process occurs in a living cell and that Hsp104 is the culprit.
“To understand how fragmentation speeds the spread of prions, think of a dandelion,” Serio said. “A dandelion head is a cluster of flowers that each carries a seed. When the flower dries up and the wind blows, the seeds disperse. Prion protein works the same way. Hsp104 acts like the wind, blowing apart the flower and spreading the seeds.”
Serio said that prions still multiply without fragmentation. However, she said, they do so at a much slower rate. So a drug that blocked the activity of Hsp104 could seriously slow progression of prion-related diseases.
Former graduate student Prasanna Satpute-Krishnan and research associate Sara Langseth, also in Brown’s Department of Molecular Biology, Cell Biology and Biochemistry, conducted the work with Serio.
The National Cancer Institute, the National Institute of General Medical Sciences, and the Pew Scholars Program in the Biomedical Sciences funded the research.
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