Caughey B, Kocisko DA.
Prion diseases: a nucleic-acid accomplice?.
Nature. 2003 Oct 16;425(6959):673-4.
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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.
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)?