A classic case of scientific serendipity has added an ironic wrinkle to the prion story. An article in today's Nature shows intriguing evidence that prions may indeed need nucleic acids to infect hosts-yet these nucleic acids may come from the host itself.

For years, scientists have fiercely argued the question of whether nucleic acids are involved in prion infection, and a Nobel Prize appeared to sanction Stanley Prusiner's renegade idea that they are not. The preponderance of evidence for the prion hypothesis-that prion proteins, unlike viruses and bacteria, are infectious vectors lacking either DNA or RNA-comes from in-vitro studies, leaving some reasonable doubt. It has been noted that there is no convincing in-vivo evidence of experimental transmission by a pathogenic prion protein. Also, the amounts of prion converted to the pathogenic form in-vitro are quite low relative to stoichiometric predictions.

Some researchers suggest that one or more cofactors required for transmission must be missing from current in-vitro models. Surachai Supattapone, Nathan Deleault, and Ralf Lucassen of Dartmouth Medical School in Hanover, New Hampshire, were on the trail of cofactors that might boost the conversion of normal prion protein (PrPc) to the protease-resistant form (PrPres) postulated to represent the pathogenic prion. Surprisingly, they found that an enzyme that degrades single-stranded RNA had the opposite effect, abolishing the limited prion conversion already seen in their brain homogenates. Since this is not the case with enzymes that degrade double-stranded RNA, RNA/DNA hybrids, or DNA, the researchers realized that single-stranded RNA might be playing a role in the conversion of PrPc to PrPres.

In a series of experiments, the researchers established that, in fact, single-stranded RNA could not only restore the abolished conversion, but could substantially increase the PrPres normally produced in their in-vitro assays. Most of the activity seems to come from RNA molecules longer than 300 nucleotides. Moreover, RNA from mice or hamsters (brain or liver) could boost PrPres production in the hamster-brain homogenate, but not RNA from invertebrates.

So what does this mean for the prion hypothesis? As Byron Caughey and David Kocisko of the NIAID/NIH Rocky Mountain Laboratories in Hamilton, Montana, point out in their accompanying editorial, there is still room to argue that in the "real world" of transmissible spongiform encephalopathies, the vector brings along its own RNA cofactor. But serious consideration must be given to the possibility that host-cell RNA is the key. Caughey and Kocisko speculate on what this might mean in vivo. Given that RNA is usually found in the nucleus and cytoplasm, and PrP outside the cell or inside organelles, they suggest, maybe RNA only plays this role in vitro, as a surrogate. In vivo, other large polyanions such as sulphated glycosaminoglycans may be the cofactor.

An obvious question at this point is whether this is relevant to other proteopathies such as Alzheimer's, Parkinson's, or Huntington's diseases? The Alzforum invites our readers to comment on whether they know of any hints that RNA is involved in the abnormal aggregation of Aβ, α-synuclein, polyQ proteins, or SOD.

In related news, a report posted yesterday to the online edition of Nature offers an explanation for how infectious prions make their way to the nervous system in the first place. It is known that prions infect peripheral organs first, followed by rapid replication in lymphoid organs, and then the nervous system. Adriano Aguzzi and colleagues in Switzerland, the U.S., and Germany now show evidence that the critical last step may take place between follicular dendritic cells (FDCs) and sympathetic nerve endings, perhaps as FDCs degenerate and spill prions out into contact with adjacent nerve endings. Alternatively, other cells may traffic prions between FDCs and nerves.—Hakon Heimer


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Comments on this content

  1. Aggregation of protein tau is strongly catalysed by polyanions, including mRNA but also polyglutamate and heparin and glycosaminoglycans ... That is in vitro! In vivo, in the cytosol or axon, protein tau probably sees so much polyanions that one wonders how it can remain "single" !? Likely, under normal conditions most protein tau is bound to microtubules or membranes.
    Self-aggregation of protein tau requires hyperphosphorylation and conformational changes - most likely in that order. Hyperphosphorylation increases the overall negative charge, and the contribution of the polyanions could mean the extra push into a beta-pleated conformation. Interestingly, FTD mutations would contribute on different levels: increasing the pool of unbound tau-4R, inducing changes in the conformation of tau and lowering its affinity for binding to the microtubules. All effectively increasing the pool of free protein tau can be phosphorylated and that will self-aggregate ... where again the polyanions might kick in.

  2. This is a very interesting study that provides some intriguing new possibilities about cellular factors involved in prion conversion. The data are very clear and fit well with some of our own results. These findings are important not only to understand the mechanism of prion conversion, but also, they will certainly help on increasing the sensitivity of diagnostic methods based on PrPres amplification. It remains to be investigated whether RNA is doing the same job in vivo or, as suggested in the accompanying article by Caughey, it is something that works only under in-vitro conditions. There are at least three important questions that need to be addressed as a follow up of this article. First, how and where does PrP meet with RNA molecules? Second, what is the mechanism by which RNA enhances prion conversion? Third, how do we explain RNA specificity (mammalian RNA works, while invertebrate RNA does not)?


External Citations

  1. Nobel Prize

Further Reading

Primary Papers

  1. . RNA molecules stimulate prion protein conversion. Nature. 2003 Oct 16;425(6959):717-20. PubMed.
  2. . Prion diseases: a nucleic-acid accomplice?. Nature. 2003 Oct 16;425(6959):673-4. PubMed.
  3. . Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature. 2003 Oct 30;425(6961):957-62. PubMed.