PrP Perturbations and TSE Infectivity

Although PrP-res is associated with TSE infectivity and has, at the biochemical level at least, some limited self-propagating activity, important questions remain about the PrP-only prion model for the TSE agent. For instance, why has no one been able to demonstrate the model s most basic prediction, that is, that PrP-sen alone can be induced to convert to an infectious agent that causes TSE disease when inoculated into animals Inoculation of a synthetic PrP peptide has induced a TSE-like disease in transgenic mice expressing a familial TSE associated mutant PrP, but the serial transmissibility of this disease remains to be determined (Kaneko et al, 2000). Why are 100,000 PrP-res molecules present per infectious unit Why is PrP-res not always found in infectious tissues (Lasmezas et al, 1997) Why are nucleic acids (Akowitz et al, 

polysaccharide (Appel etal, 1999), and lipids (Klein et al, 1998) common contaminants of PrP-res preparations and what role might they play in infectivity Why has cell-free conversion of PrP-sen by PrP-res been limited to substoichiometric yields Since these unanswered questions may have purely technical explanations, they do not negate die potential for PrP-res to act as a self-propagating prion. However, they indicate that fundamental mysteries remain about molecular mechanisms of TSE disease. 

The development of effective treatments for TSE diseases remains problematic. A number of compounds have been identified that can prolong the lives of scrapie-infected rodents if administered before or near the time of infection. These compounds include various polyanions (e.g., pentosan polysulfate (Kimberlin and Walker, 1986 Lado- 

porphyrins, and phthalocyanines (Priola et al., 2000). Unfortunately, these compounds do not appear to cross the blood-brain barrier and have no effect if administered after the infection has entered the central nervous system. Polyene antibiotics (e.g., amphotericin B and MS8209) have been shown to have beneficial effects much later in the course of infection, but still have little or no effect after the appearance of clinical disease (Demaimay et al., 1994 Adjou et al, 1995 Demaimay et al., 1997 Demaimay et al, 1999). Furthermore, the amphotericins tend to be too toxic for application to TSF diseases in humans. Other compounds such as the beta breaker peptides (Soto et al, 2000) and anthracycline (Tagliavini et al, 1998) can neutralize infectivity if incubated directly with the inoculum before inoculation, but are not known to be effective if given to the host postinoculation. Thus, there is still a dire need for effective anti-TSE drugs. 

Bolton, D.C. and Bendheim, RE. (1988). /k Novel Infectious Agents and the Central Nervous System, (G. Bock andj. Marsh, Eds), pp. 164—181, John Wiley 8c Sons, Chichester. Borchelt, D.R., Scott, M., Taraboulos, A., Stahl, N., and Prusiner, S.B. (1990)./. Cell Biol no, 743-752. 

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