Protease-sensitive prion species in neoplastic spleens of prion-infected mice with uncoupling of PrPSc and prion infectivity

Abstract

Prion diseases are fatal neurodegenerative disorders. An important step in disease pathophysiology is the conversion of cellular prion protein (PrPC) to disease-associated misfolded conformers (PrPSc). These misfolded PrP variants are a common component of prion infectivity and are detectable in diseased brain and lymphoreticular organs such as spleen. In the latter, PrPSc is thought to replicate mainly in follicular dendritic cells within spleen follicles. Although the presence of PrPSc is a hallmark for prion disease and serves as a main diagnostic criterion, in certain instances the amount of PrPSc does not correlate well with neurotoxicity or prion infectivity. Therefore, it has been proposed that prions might be a mixture of different conformers and aggregates with differing properties. This study investigated the impact of disruption of spleen architecture by neoplasia on the abundance of different PrP species in spleens of prion-infected mice. Although follicular integrity was completely disturbed, titres of prion infectivity in neoplastic spleens were not significantly altered, yet no protease-resistant PrPSc was detectable. Instead, unique protease-sensitive prion species could be detected in neoplastic spleens. These results indicate the dissociation of PrPSc and prion infectivity and showed the presence of non-PrPSc PrP species in spleen with divergent biochemical properties that become apparent after tissue architecture disruption.

Myositis facilitates preclinical accumulation of pathological prion protein in muscle

“…Similar findings have recently been reported in the brain [47] and spleen [38]. Thus, our data expand the range of tissues where PrP Sc and prion infectivity are not congruent and support the concept that non-PrP Sc species considerably contribute to prion infectivity [47, 48].…”

“…Nevertheless, presence of prion infectivity does not strictly correlate with PK-resistant PrP Sc load and protease-sensitive PrP Sc species harbor significant amounts of prion infectivity [38]. Thus we assessed prion titers of muscle and spleen by bioassay (Figure 4c).…”

Roles of endoproteolytic α‐cleavage and shedding of the prion protein in neurodegeneration

“…Prion diseases, including Creutzfeldt‐Jakob disease in humans, scrapie of sheep and bovine spongiform encephalopathy of cattle, are transmissible and fatal neurodegenerative conditions caused by the misfolding of the cellular prion protein (PrP C ) into its pathogenic, β‐sheet‐rich isoform (PrP Sc ) which is partially proteinase‐K‐resistant and tends to aggregate . The conversion of PrP C to PrP Sc by conformational replication in a templated fashion is at the basis of disease development and can be caused by a sporadic event, by mutations within the PRNP gene coding for PrP C , or by exposure to the infectious agent termed ‘prion’ of which PrP Sc is thought to be an essential component . In recent years it has become obvious that PrP Sc formation, prion propagation and transmissibility, on the one hand, and neurotoxicity giving rise to prion pathogenicity, on the other hand, are two related but distinct mechanistic aspects of the same disease .…”

“…Moreover, shedding of PrP Sc into body fluids such as cerebrospinal fluid and blood may enhance transmissibility . These two contradictory aspects would nicely reflect, yet not solely explain, the concept of the mechanistic separation of neurotoxicity and prion propagation . In fact, prion infection of transgenic mice expressing anchorless, secreted PrP C was characterized by extreme prolongation until onset of clinical signs of prion disease despite extensive PrP Sc formation .…”

Exosomes and the Prion Protein: More than One Truth

“…Its partial resistance to proteinase K digestion is used as a diagnostic tool in prion diseases. However, it should be noted that protease sensitive prion species exist and that the relation between PK-resistant PrP Sc and prion infectivity is not linear (Manson et al, 1999; Krasemann et al, 2013). A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy (Manson et al, 1999) and it is hypothesized that more than one prion species exist.…”