Source : Scripps Research Institute
JUPITER,
FL, February 9, 2012 – Scientists from the Florida campus of The Scripps
Research Institute have identified a single prion protein that causes neuronal
death similar to that seen in “mad cow” disease, but is at least 10 times more
lethal than larger prion species.
This
toxic single molecule or “monomer” challenges the prevailing concept that neuronal damage is linked to the toxicity of prion protein
aggregates called “oligomers.”
The
study was published this week in an advance, online edition of the journal Proceedings of the National Academy of
Sciences.
“By
identifying a single molecule as the most toxic species of prion proteins,
we’ve opened a new chapter in understanding how prion-induced neurodegeneration
occurs,” said Scripps Florida Professor Corinne Lasmézas, who led the new study.
“We didn’t think we would find
neuronal death from this toxic monomer so close to what normally happens in the
disease state. Now we have a powerful tool to explore the mechanisms of
neurodegeneration.”
In
the study, the newly identified toxic form of abnormal prion protein, known as
TPrP, caused several forms of neuronal damage ranging from apoptosis (programmed
cell death) to autophagy, the self-eating of cellular components, as well as
molecular signatures remarkably similar to that observed in the brains of
prion-infected animals. The study found the most toxic form of prion protein
was a specific structure known as alpha-helical.
New Paths to Explore
In
addition to the insights it offers into prion diseases such as “mad cow” and a
rare human form Creutzfeldt-Jakob disease, the study opens the possibility that
similar neurotoxic proteins might be involved in neurodegenerative disorders
such as Alzheimer’s and Parkinson diseases.
In
prion disease, infectious prions (short for proteinaceous
infectious particles), thought to be composed solely of protein, have the
ability to reproduce, despite the fact that they lack DNA and RNA. Mammalian
cells normally produce what is known as cellular prion protein or PrP; during
infection with a prion disease, the abnormal or misfolded protein converts the
normal host prion protein into its disease form.
Lasmézas
explains that prion diseases are similar to Alzheimer's and other protein
misfolding diseases in that they are caused by the toxicity of a misfolded host
protein. Recent work, as reported in The
New York Times, also found that diseases such as Alzheimer's resemble prion
diseases by spreading from cell to cell.
The
new study adds another twist. “Until now, it was thought that oligomers of
proteins are toxic in all these diseases,” Lasmézas said. “Since we found for
the first time that an abnormally folded monomer is highly toxic, it opens up
the possibility that this might be true also for some other protein misfolding
diseases as well.”
The
first author of the study, “Highly Neurotoxic Monomeric α-Helical Prion Protein,”
is Minghai Zhou of Scripps Research. Other authors include Gregory Ottenberg
and Gian Franco Sferrazza also of Scripps Research. For more information on the
study, see http://www.pnas.org/content/early/2012/02/07/1118090109.abstract
The
study was supported by the State of Florida.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu.
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