Another piece of the prion puzzle

The prion hypothesis — that spongiform encephalopathies are caused and transmitted by a misfolded prion protein — has been accepted for some time, but has not yet been proved. Now, research published in Science takes us a step closer to proving the infectivity of prion protein. Legname et al. report that synthetic mammalian prions cause disease when they are transferred to transgenic mice.

Legname et al. used Escherichia coli to produce recombinant mouse prion protein (recMoPrP), which they polymerized into amyloid fibrils, creating the synthetic prions. Intracerebral injection was used to administer these synthetic prions to transgenic mice that expressed very high levels of cellular prion protein (PrP^C). The mice subsequently developed neurological disease, although with a long incubation period of between 380 and 660 days. Control mice, inoculated with phosphate-buffered saline, did not develop symptoms of neurological dysfunction after 620 days.

The authors then took prions from the brains of mice infected with the synthetic prion and transferred them to transgenic and wild-type mice. This resulted in disease in both types of mice, and, although the incubation period was longer in wild-type mice, the incubation period in all the mice was considerably shorter than that of the mice that received the original synthetic prions.

Legname et al. point out that as the amino-acid sequence used in creating the synthetic prion did not contain the asparagine-linked oligosaccharides or the glycosylphosphatidylinositol anchor of the prion, these parts are not required for infectivity, although this does not mean that they have no influence on infectivity.

The authors conclude that all that seems to be required for the spontaneous formation of prions in any mammal is host prion protein. They propose that no additional agent is needed, which would explain the pathogenesis of sporadic Creutzfeld–Jakob disease. However, tangible evidence to back up these theories and prove the prion hypothesis requires further research. The real test is whether synthetic prions can cause disease when injected into wild-type mice, which express a much lower level of PrP^C than the transgenic mice used here.