Scripps Research Logo

Mad Cow / Creutzfeldt-Jakob Disease

Description
Creutzfeldt-Jakob Disease (CJD) is a form of progressive dementia characterized by loss of nerve cells and degeneration of nerve cell membranes leading to the production of small holes in the brain. It is rare, degenerative, and invariably fatal. Related to "mad cow disease," there is no treatment or cure. CJD usually has rapid onset and decline. Early symptoms include lapses in memory, mood swings similar to depression, lack of interest and social withdrawal. The person may become unsteady on his/her feet. Later symptoms may include blurred vision, sudden jerking movements and rigidity in the limbs. The person may experience slurred speech and have difficulty swallowing. Eventually, movement and speech are lost.

Who is at Risk?
Both men and women can be affected by CJD. The usual age of onset is 45-75 years. Typically, onset of symptoms occurs about age 60. CJD is a very rare disease, affecting only about one in every million members of the population worldwide. In the United States, CJD is thought to affect about 250 people each year.

Sources: Alzheimer Society, National Institute of Neurological Disorders and Stroke, The University of Melbourne, The Thomson Corporation

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.

For more information >

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.

For more information >

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.

For more information >

Study Reveals Structural Dynamics Of Single Prion Molecules
Using a combination of novel technologies, scientists at The Scripps Research Institute and the Whitehead Institute for Biomedical Research have revealed for the first time a dynamic molecular portrait of individual unfolded yeast prions that form the compound amyloid, a fibrous protein aggregate associated with neurodegenerative diseases such as Alzheimer's disease and variant Creutzfeldt-Jacob disease - the human version of mad cow disease. The new findings offer significant insights into normal folding mechanisms as well as those that lead to abnormal amyloid fibril conversion. The new insights may lead to the discovery of novel therapeutic targets for neurodegenerative diseases. Intriguingly, certain prions and amyloids can play beneficial roles. The subject of the new study, Sup35, enables protein-based inheritance in yeast. When this prion protein misfolds, it converts into self-perpetuating amyloid fibrils, thus altering its function in an inheritable manner. The research team used a combination of advanced biophysical methods to investigate these processes.

By focusing on single unfolded prions, the scientists were able to define the dynamics of two distinct regions or domains that determine conversion dynamics. Ashok A. Deniz, Ph.D., a Scripps Research scientist, led the study. His research techniques can now be used to probe the structures of other amyloidogenic proteins. This could prove important in understanding the basic biology of amyloid formation, as well as in designing strategies against misfolding diseases. Interestingly, the new study revealed that yeast prion protein Sup35 lacks a specific, static structure in its native collapsed state. Instead, the compact protein fluctuates among several different structures before forming intermediate shapes during the amyloid assembly process. The intermediate stages of the process are critically important. No single native unfolded protein is capable of initiating the amyloid cascade because of this constant shape-shifting. To start the amyloid conversion process, it has to first convert to an intermediate species, consisting of multiple protein molecules. This insight may be important to finding potential new therapeutic targets for disease-causing amyloids.

For more information >

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.

For more information >