Prion Strain Diversity

Abstract

Prion diseases affect a wide range of mammal species and are caused by a misfolded self-propagating isoform (PrP) of the normal prion protein (PrP). Distinct strains of prions exist and are operationally defined by differences in a heritable phenotype under controlled experimental transmission conditions. Prion strains can differ in incubation period, clinical signs of disease, tissue tropism, and host range. The mechanism by which a protein-only pathogen can encode strain diversity is only beginning to be understood. The prevailing hypothesis is that prion strain diversity is encoded by strain-specific conformations of PrP; however, strain-specific cellular cofactors have been identified in vitro that may also contribute to prion strain diversity. Although much progress has been made on understanding the etiological agent of prion disease, the relationship between the strain-specific properties of PrP and the resulting phenotype of disease in animals is poorly understood.

Cofactor and glycosylation preferences for in vitro prion conversion are predominantly determined by strain conformation

“…How unique PrP Sc conformations give rise to specific strain properties remains a mystery. Interestingly, the same PrP Sc amino acid sequence is capable of producing several different prion strains, all representing different PrP Sc conformations within the same host species [8,9], indicating that prion strain properties must be encoded by factors other than PrP sequence.…”

“…(3) superior colliculus, (4) hypothalamus, (5) thalamus, (6) hippocampus, (7) septum, (8) retrosplenial and adjacent motor cortex, and (9) cingu-lated and adjacent motor cortex. (TIF) Three-round sPMCA reactions using mouse recombinant (rec)PrP substrate, mouse cofactor recPrP Sc seed, and purified phospholipid cofactor were performed as previously described [16], in the presence of varying concentrations of synthetic poly(A) RNA, as indicated.…”

Cellular Models for the Study of Prions

“…In contrast, amyloid preparations that simply have distinct conformations in vitro (which may or may not produce different pathologies on inoculation in vivo), or consist of mixed conformational assemblies, are not bona fide strains unless they stably propagate these characteristics in living systems. Experimental data strongly support the idea that unique conformational states, or strains, of the PrP Sc amyloid underlie the myriad prion-disease clinical syndromes (e.g., Bartz 2016;Ghaemmaghami 2016. ) In recent years, the strain concept has been extended to common amyloid disorders.…”

Effects of peptidyl-prolyl isomerase 1 depletion in animal models of prion diseases

“…Once misfolded, PrP Sc can acquire different abnormal conformations [5] also referred to as prion strains. Each conformer is associated with peculiar clinical, neuropathological and biochemical alterations [6]. A prion strain can be identified either neuropathologically considering (i) the incubation and survival time [7], (ii) the clinical signs, (iii) the pattern of PrP Sc deposition [8] and the severity of spongiform changes [9]; or biochemically after PK digestion according to: (i) the electrophoretic mobility of the unglycosylated PrP band, (ii) the glycoform ratio [10], (iii) the resistance to PK digestion [11] and (iv) the conformational stability using chaotropic agents (e.g.…”