Prions molecular mechanism

The antimalarial drug quinacrine and some phenothiazine derivatives, acepro-mazine, chlorpromazine, and promazine, have been used for the treatment of prion diseases (Doh-ura et al., 2000 Korth et al., 2001 May et al., 2003). The molecular mechanism associated with the inhibition of PrPsc formation by quinacrine remains unknown. However, it is proposed that quinacrine binds with human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix 3 (Vogtherr et al., 2003) and provides neuroprotection. Quinacrine may also act as an antioxidant and reduce the toxicity of prP 6 (Turnbull et al., 2003). 

Abstract Here we review the known strain profiles of various prion diseases of animals and humans, and how transgenic mouse models are being used to elucidate basic molecular mechanisms of prion propagation and strain variation and for... 

DeMarco ML, Daggett V (2007) Molecular mechanism for low pH triggered misfolding of the human prion protein. Biochemistry 46 3045... 

Conversion from the [PS7+] to the [psi ] state is known as curing. While this phenomenon occurs spontaneously at a low frequency (Cox, 1965), both chemical and biological factors that increase curing rates have been identified. New information is emerging on the molecular mechanisms by which these treatments act, and these studies provide new insights into the prion replication process in vivo. 

This long quest was marked by milestones. As already discussed, the obtention of highly purified preparations of infectious scrapie particles was necessary to identify the PrP protein. Circular dichroism studies of PrP and PrP demonstrated the existence of two totally distinct conformations of PrP, one corresponding to the physiologically expressed brain protein and the other to the infectious protein. However, the masterly demonstration of the mechanism of prion replication is that PRNP° mice, which do not express the PrP protein, failed to propagate prion infectivity. Hence, without the brain reservoir of normal PrP proteins, infectious PrP proteins are harmless and unable to cause any disease. If we link this information with the respective structures of PrP and PrP , then we have a molecular mechanism accounting for the replication, by force, of prions invaders in the brain of healthy animals (Fig. 9.5). 

FIGURE 9.5 Molecular mechanism of prion replication. A healthy PrP protein, chiefly a-hehcal, binds to an infectious PrP protein that has a high p-strand and low ce-heHx content. This physical contact, which has been compared to a "kiss of death," induces a major conformational change in PrP corresponding to the a p transition. 

All three of these predictions from this minimal model are manifest in the etiology of prion disease an inversely proportional relationship between PrPc expression and prion incubation period in transgenic mice predisposition by relatively subtle mutations in the protein sequence and a requirement for molecular homogeneity between PrPSc and PrPc for efficient prion propagation [4, 5, 20]. It is clear that a full understanding of prion propagation will require knowledge both of the structure of PrPc and PrPSc and of the mechanism of conversion between them. 

Lindquist, S., and E. C. Schirmer (1999). The role of Hspl04 in stress tolerance and prion maintenance. In Molecular Chaperones and Folding Catalysts. Regulation, Cellular Function and Mechanisms (B. Bukau, ed.),pp. 347-380. Harwood Academic Publishers, Amsterdam. 

This volume, the brainchild of two major figures in protein chemistry, David Eisenberg and Peter Kim, covers our current understanding of these cellular components/machines, with an emphasis on their mechanisms of action. In addition, there is a chapter on protein misfolding in prion disease in a yeast system, with some attention given to the influence of molecular chaperones on that process, and one on a system analysis of response to ER stress. 

Lasmezas, C.I., and Weiss, S. (2000). Molecular biology of prion diseases. In Microbial Foodborne Diseases. Mechanisms of Pathogenicity and Toxin Synthesis. Cary, J.W., Linz, J.E. and Bhatnagar, D., eds. pp. 495-537. Technomic Publishing Co., Inc., Lancaster. 

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