Tubulovesicular structures: what are they really?

The tubulovesicular structures (TVS) are the only structures unique at the level of thin-section electron microscopy for all TSEs so far examined. They were first described in NIH Swiss mice infected intracerebrally with the "Chandler" strain of scrapie by David-Ferreira et al. in 1968 [Proc. Soc. Exp. Biol. Med. 127:313-320]. TVS were described as "particles and rods ranging in diameter from 320 to 360 A(o)." The exact topology of TVS is not entirely clear. In most published electron micrographs, TVS appeared as spheres measuring between 20 and 40 nm in diameter. The number of neuritic processes containing TVS increases through the incubation period and has been shown to correlate with the incubation period and titre of infectivity in three longitudinal disease studies of scrapie and CJD. These studies, therefore, suggest that TVS may represent a primary pathogenetic event rather than a pathological product of disease. The predominant theory of the scrapie agent is now the "prion hypothesis" and its derivatives, which implies that a conformationally altered abnormal isoform (PrP(Sc) or PrP*) of a normal cellular membrane glycoprotein (PrP(c)) is the agent and its accumulation merely mimicks replication. If an abnormal fraction of PrP is indeed the infectious agent, (although it is no longer suggested in some quarters that protease resistant fraction of PrP(Sc) is the agent). The absence of stainable PrP in TVS, however, would indicate that they are not the ultrastructural correlate of the agent. However, TVS appear to be specific and unique to the TSEs, appearing before the earliest pathological changes and increasing in line with incubation period or titre. The very existence of TVS and their correlation with infectivity, therefore, urgently needs an explanation.