Test-tube 'prions' could advance study of mad cow disease
Scientists at UCSF have created synthetic prions -- tiny protein particles -- and shown they can cause brain disease in laboratory animals and replicate without any genetic material inside them.
The achievement could lead to new tools for early detection of the faulty forms of prions that are known to cause mad cow disease in cattle and the rare, apparently spontaneous Creutzfeld-Jakob disease in humans, the researchers say.
The work may also advance research into more common degenerative nervous system disorders such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis, known commonly as Lou Gehrig's disease, according to the UCSF scientists.
The new research is being reported today in the journal Science by Dr. Giuseppe Legname, a neurologist in the laboratory of senior author Dr. Stanley Prusiner, who won the Nobel Prize for his discovery of prions nearly 25 years ago and has been working on their puzzles ever since.
Prusiner's "prion hypothesis" has long provoked controversy among some scientists who have challenged his contention that the proteins alone, if they became folded into structures far different from normal prions, could actually reproduce themselves and cause disease even though they contain no DNA or RNA, the basic molecules of heredity.
Normal prions (pronounced pree-ons) are harmless proteins found in all mammals where they have been sought. The problems arise when they become folded into abnormal shapes, leading to scrapie in sheep, bovine spongiform encephalopathy or mad cow disease in cattle, and similar brain diseases in deer, elk and mink.
The misfolded proteins have also been shown to cause the same abnormal folding in other nearby normal proteins -- just as if they were infectious agents like viruses or bacteria, according to Prusiner.
As part of the new study, Prusiner, Legname and their colleagues created a large fragment of a normal prion protein and folded it using lab techniques into an abnormal shape, which they suspected would give it the infectious properties of the faulty proteins.
Then they injected the faulty prion fragments into the brains of mice that had been genetically engineered to produce copious quantities of normal prions.
In little more than a year, the first of the genetically engineered lab mice developed typical prion brain disease, and by the end of two years, all the mice in the colony contracted the same disease.
The researchers then took brain tissue from one of the sick mice and inoculated normal wild-type mice with an extract of the tissue. In less than six months, these mice, too, developed brain disease, Prusiner and his colleagues reported.
The disease symptoms in the mice were typical of many degenerative nervous systems in humans, Prusiner said in an interview: The mice became rigid, they staggered and wobbled, and they appeared to become hunchbacked.
Ultimately, Prusiner said, the ability to "create prions in the test tube" could enable his team to determine the detailed structure of misfolded prions for the first time; to develop a test for rapidly detecting the disease- causing prions, and ultimately, perhaps, to find ways of preventing and even treating the degenerative nervous system diseases caused by the faulty prions.
One of the signs of many degenerative brain diseases is the development of tangles of fibers in the brain known as amyloid plaques, caused by the abnormal prions, and in the experiments the UCSF team is reporting, those amyloid plaques were found in the brains of all the sick mice.
"The findings represent a renaissance in prion biology," Prusiner said in a statement released by UCSF. "For the first time, we can create prions in the test tube, which will change the way scientists do experiments in the field. We now have a tool for exploring the mechanism by which a protein can spontaneously fold into a shape that causes disease."
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