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Abstract & Commentary
Synopsis: The means by which prions cause neuropathologic damage remains to be established.
Source: Legname G, et al. Synthetic Mammalian Prions. Science. 2004:305;673-676.
The cause of diseases such as Jakob-Creutzfeldt and mad cow disease is of great interest. These illnesses were initially designated as slow viral infections. A viral etiology and infective DNA however, has never been established for any of these illnesses. Stanley Prusiner developed a theory that these diseases are caused by conformationally altered proteins, termed prions. It was suggested that the infectious prions, which had an altered conformation, interacted with normal prions in the brain, resulting in conversion of the normal prions to the mutant form. This was particularly the case when the prions developed a beta-pleated sheet structure consistent with amyloid. The prion hypothesis however, has been strongly debated, despite Dr. Prusiner having received the Nobel Prize for this work. The last missing piece of evidence has been to demonstrate that recombinant mouse prion protein can be infectious in mice. In the present study, recombinant mouse prion protein was produced by Escherichia coli and then polymerized into amyloid fibrils, that represent a subset of beta pleated sheet-rich structures. The fibrils, containing the recombinant prion, were then inoculated intracerebrally into mice that overexpress normal prions at 16 times the normal levels. The mice were injected with either unseeded or seeded prion proteins. The seeded ones were ones that were induced to take on more amyloid in vitro. The mice developed neurologic dysfunction between 380 and 660 days after inoculation. Brain extracts showed protease-resistant prions by Western blotting. These extracts were then transmitted to wild-type FVB mice and transgenic mice, overexpressing PrP with incubation times of 150 and 90 days, respectively. These mice showed typical neuropathology of prion disorders consisting of vacuolization and gliosis.
These experiments appear to be the first to establish that recombinant prions can be infectious in mice. They, therefore, provide the crucial missing link to verify the prion hypothesis. They are not absolute, since the initial infectivity was shown in a transgenic mouse overexpressing normal prions. Nevertheless, these experiments are very convincing that prions can indeed transfer infectivity in mice. The means by which prions cause neuropathologic damage, however, remains to be established. — M. Flint Beal
Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.