Brown Team Finds Crucial Protein Role in Deadly Prion Spread
http://www.brown.edu/Administration/News_Bureau/2006-07/06-084.html
January 23, 2007
Contact: Wendy Lawton
(401) 863-2476
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Brown University biologists have made another major advance toward
understanding the deadly work of prions, the culprits behind fatal brain
diseases such as mad cow and their human counterparts. In new work
published online in PLoS Biology, researchers show that the protein
Hsp104 must be present and active for prions to multiply and cause disease.
PROVIDENCE, R.I. [Brown University] --- 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.
Editors: Brown University has a fiber link television studio available
for domestic and international live and taped interviews and maintains
an ISDN line for radio interviews. For more information, call the Office
of Media Relations at (401) 863-2476.
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