More Problems for Prion Proponents
Probably.
Laura Manuelidis and her colleagues at Yale continue to chip away at the idea that prions—proteinaceous infectious particles—cause transmissible spongiform encephalopathies (TSEs) all by themselves. (For background on this story, start here.) Her group's latest work to undermine the prion hypothesis, for which Stanley Prusiner received the Nobel Prize in 1997, was somewhat stealthily published in the August 11th issue of PNAS.
According to the prion hypothesis of disease, the normal, endogenous form of prion protein (PrP) misfolds to become infectious. (This abnormal, disease-associated form of PrP, which is resistant to degradation, is denoted PrP-res.) PrP misfolding may occur spontaneously, through genetically encoded triggers, or by the inoculation or ingestion of misfolded PrP from infected tissues. The last method is apparently how kuru, sheep scrapie, and variant Cretuzfeld-Jacob disease (or vCJD, from bovine spongiform encephalopathy [BSE]) are propagated.
The prion hypothesis also stipulates that conversion of normal PrP into PrP-res is only possible when there is considerable homology between the donor and host PrP. But, as Manuelidis points out, this idea has not been consistently supported by animal experiments. For instance, the vCJD agent has been readily transmitted to normal mice but not to transgenic mice that expressed only human PrP. Data also show that PrP-res Western-blot profiles do not vary with different infectious TSE agents, as would otherwise be expected.
Other problems with the prion hypothesis include the inability to demonstrate the reliable infectivity of purified PrP-res and the fact that tissue samples without PrP-res can transmit infection. Arguably the most heretical aspect of the prion hypothesis is that the infectious agent, unlike bacteria or viruses, does not contain nucleic acid—that is, DNA or RNA.
For these reasons, it remains difficult for many to wholeheartedly embrace the prion hypothesis, despite its now wide acceptance within the scientific community.
Contradicting the proposal that donor and host PrP must be homologous to transmit TSE, Manuelidis et al showed in PNAS that high levels of murine wild-type PrP did not prevent the transmission of primate kuru to mice. Instead high levels of murine wild-type PrP shortened the incubation time of disease—a phenomenon that would be expected if PrP acts as a viral receptor, she argued. Mouse experiments with the infectious agents for sporadic CJD, BSE, and scrapie also showed incubation times, pathologic features in the brain and spleen, and animal behaviors that were distinct from those of kuru.
Ultimately Manuelidis proposes that host PrP is required for TSE infection, but that it probably acts as a receptor or "scaffold" for the true infectious agent—which is possibly a 25-nm virus-like particle, at least in the case of scrapie.
