Prions have been on the move lately. Not only is the path of the infectious agent now being traced from immune cells to nerve cells, but prions have found a new accomplice that appears to be a nucleic acid. Researchers have also found a way to experimentally reverse the first signs of brain damage that afflict mice infected with scrapie prions.

Credit: EM Unit, VLA/Science Photo Library

In the 16 October Nature, Nathan Deleault et al. provide evidence that conversion of the normal form of the prion protein (PrPc) to the pathogenic form (PrPsc) is greatly enhanced by an RNA intermediate. The results hark back to an earlier time when researchers sought in vain to implicate a nucleic acid–containing agent in transmissible spongiform encephalopathies (TSEs). But in this case, the RNA does not seem to encode the infectious agent itself. Rather, the RNA appears to aid in the protein-folding process that transforms PrPc into PrPsc and PrPsc aggregates (aggregates shown here).

Prion researchers have long suspected that prions have a sidekick. Conversion of PrPc to PrPsc occurs only ineffectively in cell-free reactions, compared with the yields obtained by mixing homegenates from normal and TSE-affected brains. Deleault et al. asked which factors in these homegenates enhance the conversion process. They found that depletion of single-stranded RNA severely hampered conversion, whereas addition of RNA boosted conversion. It remains formally possible, however, that a cofactor other than RNA acts as an intermediary—perhaps another highly negatively charged molecule.

In other news,the results of Giovanna Mallucci et al. in the 31 October Science challenge two longstanding assumptions about prion diseases: that the damage done in the brain is irreversible, and that PrPsc does most of the damage in the first place.

The investigators engineered mice to express PrPc in neurons only for the first 12 weeks of life, then inoculated the mice with scrapie prions soon after birth. As expected, the mice developed the first signs of TSE, such as spongy holes in the brain. But after 12 weeks, something unusual happened. The spongiosis disappeared and the mice went on to survive and live apparently healthy lives. In glial cells, PrPc continued to be expressed and PrPsc continued to accumulate, suggesting that conversion of PrPc to PrPsc must occur within neurons for disease to ensue. The investigators speculate that something about the conversion process itself—perhaps a toxic byproduct of PrPsc formation—might lead to disease.