Lab Experiments Reveal Potential Therapeutic Target for Degenerative Brain Diseases
Laboratory experiments on prion diseases – degenerative brain illnesses such as Kuru and Crutzfeldt-Jakob disease in humans, scrapie in sheep, and the so-called "mad cow disease" – have yielded a surprising clue to what may be a way to prevent these diseases. In the August issue of the Journal of Virology, scientists from the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues in France and the United Kingdom report that a small piece of the prion protein (PrP) prevents the larger molecule from folding incorrectly. Since abnormal folding is associated with prion disease, blocking the ability of the prion protein to assume an abnormal shape could be key to blocking progression to disease.
"Prion disease pathology requires misfolded prion proteins," comments NIAID Director Anthony S. Fauci, M.D. "This study demonstrates that, at least in a test tube, a section of the prion protein can be used to maintain proper shape. This insight opens the possibility of preventing prion diseases."
Prion diseases, officially called transmissible spongiform encephalopathies (TSEs), are uniformly fatal illnesses that cause infected brains to look like Swiss cheese at autopsy. These diseases gained widespread notoriety in the mid-1990s when 34 people in the United Kingdom developed a progressive neurological breakdown leading to death. The most commonly believed source of disease for humans is meat from "mad cows" afflicted with bovine spongiform encephalopathy (BSE).
Despite recent indications that BSE crosses from cows to humans, these infections tend to stay in the animal species where they originate. Scientists at NIAID’s Rocky Mountain Laboratories (RML) in Montana and their colleagues, for example, recently demonstrated that abnormal PrP from a mouse cannot convert normally folded PrP from a hamster. However, these investigators recognized that the PrP from the mouse, hamster, and a second strain of mouse all shared the same core region. This shared section of the PrP inhibited conversion of normal PrP to abnormal PrP in both rodent species.
"In our experiments, we showed that adding a peptide derived from the core of the prion protein dramatically reduced the generation of abnormal PrP associated with prion disease," explains lead author Joelle Chabry, Ph.D., from the Centre National de la Recherche Scientifique (CNRS) in France.
"Because the core region is very conserved in most species of prion protein," remarks senior author and RML researcher Bruce Chesebro, M.D., "this peptide may inhibit the prion protein conversions in a wide variety of animals."
Although the mechanism of inhibition is not known, the importance of the reaction lies in its potential application to actual disease. Using scrapie-infected mouse cells, the investigators blocked the production of new, abnormal PrP by incubating the cells with the core peptide. Such an approach opens possibilities for therapy in animals.
Protein shape changes associated with prion diseases protect the abnormal prion protein from breakdown by the body. The resistant proteins build up and form insoluble plaques leading to neurological problems. These effects may not appear until years or even decades later, and have been a major stumbling block for researchers. Other diseases characterized by development of plaques and that may be related to prion diseases include Alzheimers and Parkinson’s disease.
"No one would have suspected that a piece of the prion protein itself might prevent further disease," says Dr. Chesebro. "Although the research is not at the point of preventing disease in humans or, for that matter, in cows, we’re excited that this therapeutic approach might prove beneficial." Reference: J. Chabry, et al. Journal of Virology 73(8):6245-50 (1999).
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