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Scripps Research Scientists Develop New Tests that Identify Lethal Prion Strains Quickly and Accurately

Findings Will Significantly Accelerate Prion Research

LA JOLLA, CA, December 4, 2007—Scientists at The Scripps Research Institute in Jupiter, Florida, have developed a new test to identify strains of prions, infectious proteins that cause a number of diseases including "mad cow disease," and a human counterpart, variant Creutzfeldt-Jakob disease. These advances open the door to better understanding and diagnosis of these troubling conditions.

Members of the group earlier developed an in vitro test, called the Standard Scrapie Cell Assay, which measures prion infectivity levels in a highly accurate and rapid way, producing results in less than two weeks. The new test, called the Cell Panel Assay, allows researchers to quickly distinguish between several prion strains using various cells lines. The new assay is based on the scientists' finding that four different cell lines exhibited widely different responses to different strains of the infectious protein particles.

The research is being published in an advanced online edition of the Proceedings of the National Academy of Sciences the week of December 3, 2007.

"The Standard Scrapie Cell Assay vastly accelerates the measurement of prion infectivity and the determination of those cell lines that are able to sustain high infection rates of some prion strains," said Sukhvir P. Mahal, an author of the study who is a senior staff scientist in the laboratory of Charles Weissmann, chair of the Scripps Florida Department of Infectology. "The current test, which takes anywhere from 150 to 250 days and involves large numbers of laboratory mice, is slow, imprecise, and expensive. Our new assay will replace the current mouse brain-bioassay."

The current method of measurement and identification of prion strains involves injecting samples into the brains of different lines of mice and then waiting months to years to see how long it takes for the animals to succumb to disease; the higher the prion level, the less time it takes for them to become lethally infected, but the characteristic times vary for different prion strains.

In contrast, the new Cell Panel Assay is based on prion-susceptible cell lines. In the test, cells are exposed to prions and then the infected cells are identified and counted using automated imaging equipment.

A Unique Pathogen

Prions (the name stands for proteinaceous infectious particles) are unique infectious pathogens associated with some 15 different diseases, including Bovine Spongiform Encephalopathy ("mad cow") and its rare human form, variant Creutzfeldt-Jacob disease. Infectious prions, which are thought to consist mainly of an abnormally structured or misfolded protein, have the ability to reproduce, despite the fact that they contain no nucleic acid genome as do viruses or bacteria.

Mammalian cells normally produce what is known as cellular prion protein; during infection, the abnormal protein converts production of normal host prion protein to its infectious form. The full details of this process are still not understood.

Prions develop in distinct strains, classically characterized by incubation time and the pattern of brain damage that develops during infection. It is currently thought that strain-specific properties of prions are determined by the three-dimensional structure of the misfolded protein, although the amino acid sequence remains the same. Interestingly, several different prion strains can be propagated indefinitely in a single host although the host produces only one type of prion protein.

"Some cell lines can be persistently infected by prions and show preference for certain strains," Mahal said. "One intriguing finding of our new study is that a cell line's ability to replicate a particular prion strain is a trait that varies significantly among the members of the cell population—even sibling cell lines may show different relative susceptibilities to various prion strains."

This suggests that the capacity of a cell line to replicate a particular prion strain is controlled epigenetically without any changes to the DNA sequence, she said.

Another fascinating question raised by the study is how cells come to distinguish between prion strains; that is, between the various proteins that differ only in the way they are folded. The exact nature of that recognition process is now the target of a new Scripps Research study using the Cell Panel Assay.

Other authors of the study, Prion Strain Discrimination In Cell Culture: The Cell Panel Assay, include Christopher A. Baker, Cheryl A. Demczyk, Emery W. Smith, and Charles Weissmann of the Department of Infectology, Scripps Florida; and Christian Julius of the Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.

The study was supported by The Scripps Research Institute and the Alafi Family Foundation.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.




 

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