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Prion Diseases

Prions, short for "proteinaceous infectious particles," are small, pathogenic agents capable of causing transmissible spongiform encephalopathic (TSE) diseases. Humans are susceptible to several prion diseases: Creutzfeldt-Jacob Disease (CJD), Gerstmann-Straussler-Scheinker Syndrome (GSS), Fatal Familial Insomnia (FFI), and Kuru and Alpers Syndrome. In the early stages of disease, patients may have failing memory, behavioral changes, lack of coordination and visual disturbances. As the illness progresses, mental deterioration becomes more pronounced and involuntary movements, blindness, weakness of extremities and coma may occur.

Who is at Risk?
Typically, onset of symptoms occurs at about age 60 and about 90% of patients die within one year.

Source: World Health Organization

TSRI Scientists Find a Way to Block Prions that Cause Mad Cow Disease
Scientists working at TSRI and at the University of California, San Francisco, including TSRI Professor Dennis R. Burton, Ph.D. and Associate Professor R. Anthony Williamson have described an antibody that clears prion infection in cell culture. This finding may point the way to a treatment for mad cow disease and its human equivalent. The antibody stops the whole process. Prion infections are known to cause bovine spongiform encephalopathy or mad cow disease, and one form of the same disease in humans, called variant Creutzfeldt-Jakob Disease. Diseases like mad cow are unusual because unlike most infectious diseases, the infectious material is not a virus or bacteria but malformed prion protein - chemically the same as normal human proteins. The prion protein starts out with one shape that is innocuous and ends up with another shape that is deadly.

Infectious prions from an animal with mad cow disease, for instance, will initially cause normal prion proteins in the brain of a healthy cow to misform into the infectious form. Then these prions will act on more normal prion protein to produce more and more misfolded protein that accumulates and eventually leads to brain damage with a sponge-like appearance. The antibody Burton, Williamson and colleagues designed seems to halt the infection all together. The antibody, called Fab D18, binds to the normal form of prion protein and prevents the infectious form from binding in cell culture. Significantly, the normal cellular machinery degraded whatever infectious prions remained, suggesting that the antibody has the potential to cure established infection. The finding is also significant because it provides a potential therapeutic target - a highly effective human drug might be designed to bind to the same place as Fab D18.

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Focusing on Prion Diseases
Prominent Scripps Florida Professor Charles Weissmann, Ph.D., is focusing on prion diseases (spongiform encephalopathies such as mad cow disease and its human cousin, variant Creutzfeld-Jakob disease). He and his colleagues are studying the nature and components of infectious prions, asking such questions as how prions are transmitted from cell to cell and which genes contribute to susceptibility or resistance to prion infections. In recent years, Professor Weissmann has made breakthroughs in the investigation of diseases induced by prions.

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Scientists Convert Mad-Cow-Like Prion Disease into Something Like Alzheimer's
A group of researchers led by scientists at The Scripps Research Institute, including Professor Michael B.A. Oldstone, M.D., have done something unusual with prion proteins, which are the underlying cause of mad cow disease and variant Creutzfeldt-Jakob Disease in humans. Prion proteins cause these diseases as a misfolded form of the protein accumulates in the brain and interferes with numerous system functions. The researchers have described the effect of removing a stretch of amino acids at the COOH end of the protein - called the glycophosphoinositol (GPI) anchor. The GPI anchor is essential for anchoring the prion protein into the membranes of the cells, where it is believed this host prion protein interacts with the abnormal disease-producing isoform to yield more and more of the disease associated prion protein. Suspecting that this anchor may also be essential to the pathogenesis of prion diseases, the scientists removed it and looked at the effect of the removal on prion disease pathogenesis. By taking off this anchor, the researchers showed that the prion protein still folded but was no longer able to attach in normal amounts onto the surface of cells. They then looked at the effect of the anchorless prions on the disease in vivo, and they found evidence that GPI anchor plays a dramatic role in prion disease pathogenesis.

They found that the anchorless prions instead induced a disease that mimicked Alzheimer's - deposits of amyloid fibrils associated with dystrophic neurons were observed. The anchorless prion is still soluble and it still folds into a normal prion form. But the difference is that without the GPI motif, the protein cannot anchor onto the cell surface. So instead of having 95 percent of the prion proteins that are produced anchored to the cell surface, most of them wind up being secreted. Significantly, the anchorless prion proteins had a dramatic reduction in their ability to cause prion disease in vivo. Transgenic mice that express a form of prion protein without the GPI anchor no longer show the normal characteristics of prion disease when they are infected with infectious prions. In the mice with the GPI anchor removed, inoculation with tissue containing the misfolded "scrapie" form of prions failed to induce the usual clinical manifestations of prion disease, even after 600 days. By comparison, inoculation of normal mice with the same scrapie samples caused disease in 160 to 180 days.

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Scripps Research Findings Could Lead To New Treatment Approaches For Mad Cow And Creutzfeldt-Jakob Disease
Working in close collaboration with an international group of researchers, scientists at The Scripps Research Institute have shown for the first time that small clumps of abnormal prion proteins called oligomers cause the widespread death of neurons. In contrast, much larger prion aggregates known as fibrils proved to be far less toxic. The findings suggest that small protein aggregates play a central role in prion diseases; similar mechanisms have been proposed for the so-called "amyloid" neurodegenerative diseases, including Alzheimer's. The work may provide novel therapeutic approaches for treating people with these conditions.

The new study clearly establishes these misfolded prion protein oligomers as the major neurotoxic agent in both in vitro and in vivo experiments. Professor Corinne Lasmezas, Ph.D., a Scripps Research scientist in the Florida campus's Department of Infectology led the study. This new discovery reveals the most likely culprit responsible for the death of neurons associated with spongiform encephalopathies and probably other neurodegenerative diseases. The researchers posit that prion oligomers damage neurons by disturbing neuronal membranes and hence cell signaling, as well as by building up excessively within cells, eventually triggering apoptotic or programmed cell death.

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