Prions replication

Cohen, RE., et al. Structural clues to prion replication. Science 264 530-531, 1994. 

Peripheral pathogenesis involves the lymphoreticular system. Although the pathological consequences of prion infection occur in the central nervous system, and experimental transmission of these diseases is most efficiently accomplished by intracerebral inoculation, most natural infections do not occur by these means. Indeed, administration to sites other than the central nervous system is known to be associated with much longer incubation periods, which may extend to 20 years or more [5,12]. Experimental evidence suggests that this latent period is associated with clinically silent prion replication in... 

Wlrite AR, Enever P, Tayebi M, Muslren SR, Linehan J, Brandner S, Anstee D, collinge J, Hawke S (2003) Monoclonal antibodies inlribit prion replication and delay tire development of prion disease. Nature 422(6927) 80-83. 

Prusiner SB, Scott M, Foster D, Pan K-M, Groth D, Mirenda C, Torchia M, Yang S-L, Serban D, Carlson GA, Hoppe PC, Westaway D, DeArmond SJ (1990) Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63 673-686... 

The cellular prion protein mediates neurotoxic signalling of (3-sheet-rich conformers independent of prion replication. EMBO J [Epub ahead of print]... 

Fig. 5 Models of prion replication, (a) The template assistance model predicts that a PrPSo monomer is more stable than PrPc, but is kinetically inaccessible. In the rare event that a PrPSo monomer is created spontaneously (or provided exogenously), it can template the misfolding of another PrPc molecule by direct interaction. The dashed line shows that the newly created PrPSc monomer can act as another seed to formation of PrPSc. (b) The nucleation polymerization model predicts that barrier to prion protein conversion is the formation of a nucleus in which the protein adopts a PrPSo-like structure. The formation of such a low order aggregate is not favored however, once it has formed, polymerization from a pool of PrPc molecules can take place efficiently. Fragmentation of the polymer increases the number of ends for the recruitment of PrPc monomers...

Supattapone S, Bosque P, Muramoto T, Wille H, Aagaard C, Peretz D, Nguyen HOB, Heinrich C, Torchia M, Safar J, Cohen FE, DeArmond SJ, Prusiner SB, Scott M (1999) Prion protein of 106 residues creates an artificial transmission barrier for prion replication in transgenic mice. Cell 96 869... 

Charveriat M, Reboul M, Wang Q, Picoli C, Lenuzza N, Montagnac A, Nhiri N, Jacquet E, Gueritte F, Lallemand JY, Deslys JP, Mouthon F (2009) New inhibitors of prion replication that target the amyloid precursor. J Gen Virol 90 1294—1301... 

Resenberger UK, Flarmeier A, Woemer AC, Goodman JL, Muller V, Krishnan R, Vabulas RM, Kretzschmar F1A, Lindquist S, Hartl FU, Multhaup G, Winklhofer KF, Tatzelt J (2011) The cellular prion protein mediates neurotoxic signalling of 6-sheet-rich conformers independent of prion replication. EMBO J 30 2057-2070... 

Generating Transmissible Amyloids The Prion Replication Cycle. 268... 

Fig. 4 Yeast prion replication cycle. Prion fibres grow by non-covalent polymerization of prionogenic proteins. Polymer fragmentation by Hspl04 completes replication cycle...

Tipton KA, Verges KJ, Weissman JS (2008) In vivo monitoring of the prion replication cycle reveals a critical role for Sisl in delivering substrates to Hspl04. Mol Cell 32 584-591... 

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. 

Mimicking donimant negative inhibition of prion replication Direct change of PrP secondary structure Binds to extraneuronal... 

Perrier, V., Wallace, A.C., Kaneko, K., Safar, J., and Prusiner, S.B. (2000). Mimicking dominant negative inhibition of prion replication through structure-based drug design. PNAS97, 6073-6078. 

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