Prions Proven Infectious?
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Prion diseases and Alzheimer’s have some striking parallels, most notably the role played by amyloidogenic peptides. But they have many differences, too. Cruetzfeld-Jacob, scrapie, and mad cow diseases are all caused by an infectious protein, for example. Or are they? Though the prion theory of infection is now widely accepted, it has been plagued by one niggling doubt—no one has been able to show that a synthetic prion, in infectious conformation, can cause disease (see ARF related news story on the recent debate about this at the Swiss Society of Neuropathology meeting in St. Moritz). A paper in last week’s Science, however, seems to put that controversy to rest. Fittingly, the report comes from the lab of Stanley Prusiner, University of California, San Francisco, who was awarded the 1997 Nobel prize in medicine for his pioneering work on prion infection.
Joint first authors Giuseppe Legname and Ilia Baskakov, together with Prusiner lab colleagues and a collaborator at the Heinrich-Heine University, Dusseldorf, Germany, have induced neurodegeneration in mice by infecting them with a recombinant prion. As a model, the researchers chose to work with the Tg9949 mouse strain. Though these animals overexpress a fragment (amino acids 89-231) of the mouse prion protein (MoPrP), they live for over 550 days with no sign of neurodegenerative disease. However, when Legname and colleagues injected these mice intracerebrally with recombinant protein that was folded into an infectious prion conformation, all the mice tested showed neurologic dysfunction within about a year.
The infectious protein Legname and colleagues used was obtained by expressing the MoPrP fragment (residues 89-231) in Escherichia coli, then purifying it and allowing it to form amyloid fibrils. These fibrils were then used to seed fibril formation by fresh protein. Both seeded and unseeded amyloid eventually caused neurodegeneration, though the seeded preparation worked slightly faster.
The work seems to confirm the infectious nature of prions, though as Science’s Jennifer Couzin points out in an accompanying news piece, some researchers have their doubts. John Collinge, director of the Medical Research Council prion unit at University College London, for example, has previously studied rodents that express higher amounts of prion protein than normal (about 10-fold), but found that the animals get sick spontaneously—no infectious prion needed. Could Prusiner’s animals also be succumbing in a similar fashion? This seems unlikely. Though the numbers of animals used were small, all those inoculated with the amyloidogenic form of MoPrP developed disease (n=11), while those inoculated with saline (n=7) or prions from Syrian hamsters (n=8) did not.
While this work goes a long way to prove the prion theory of infection, more icing is needed on this particular cake. What researchers have not yet been able to do is use prions to induce disease in normal animals, as opposed to transgenic ones that express a lot of prion. Until that happens, there is no doubt that others will continue to search for other infectious agents that may be involved (see ARF related news story on the potential role of nucleic acids in prion disease transmission).—Tom Fagan
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Primary Papers
- Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, Dearmond SJ, Prusiner SB. Synthetic mammalian prions. Science. 2004 Jul 30;305(5684):673-6. PubMed.
- Couzin J. Biomedicine. An end to the prion debate? Don't count on it. Science. 2004 Jul 30;305(5684):589. PubMed.
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