The genetics of prions—a contradiction in terms? Prof Adriano Aguzzi, MD, Sebastian Brandner, MD  The Lancet  Volume 354, Pages S22-S25 (July 1999) DOI: 10.1016/S0140-6736(99)90245-3 Copyright © 1999 Elsevier Ltd Terms and Conditions

Figure 1 Models for the conformational conversion of PrPc into PrPSc A: the “template-directed refolding model” postulates an interaction between exogenously introduced PrPSc and endogenous PrPc, which is induced to transform itself into further PrPSc. A high energy barrier may prevent spontaneous conversion of PrPc into PrPSc B: the seeding or nucleation model proposes that PrPc and PrPSc are in a reversible thermodynamic equilibrium, Only if several monomeric PrPSc molecules are assembled into a highly ordered seed, can further monomeric PrPSc be recruited and eventually aggregate to amyloid, The likelihood of spontaneous formation of a seed is a function of the local PrPst concentration (which may be modulated by PrPSc-binding proteins) and is inversely dependent on the number of monomers needed to form a proto-seed. Within such a crystal-like seed, PrPSc becomes stabilised. Fragmentation of PrPSc aggregates increases the number of nuclei that can recruit further PrPSc and therefore results in apparent replication of the agent. The Lancet 1999 354, S22-S25DOI: (10.1016/S0140-6736(99)90245-3) Copyright © 1999 Elsevier Ltd Terms and Conditions

Figure 2 Schematic drawing of the coding region of the human PRNP gene Mutations that segregate with inherited prion diseases are shown above, as well as non-pathogenetic polymorphisms (red numbers) and silent mutations (blue). The N- terminal and C-terminal domains are signal peptides that are cleaved off during maturation of PrPc. Octarepeat regions are represented by yellow boxes, and pathogenetic octarepeat insertions of 16, 32, 40, 48, 56, 64, and 72 aminoacids are shown below. Deletion of one octarepeat stretch does not seem to segregate with a neurodegenerative disorder.19 The dark green box indicates a conserved region and 13-sheet domains are drawn in pink. There is an apparent clustering of pathogenetic mutations associated with a CJD phenotype around the α-helical domains (H1, H2, H3, dark blue), and aminoacid exchanges associated with a GSS phenotype are located further upstream around the conserved region. The Lancet 1999 354, S22-S25DOI: (10.1016/S0140-6736(99)90245-3) Copyright © 1999 Elsevier Ltd Terms and Conditions