Co-Occurrence of Types 1 and 2 PrPres in Sporadic Creutzfeldt-Jakob Disease MM1

Abstract

The genotype (M/M, M/V, or V/V) at polymorphic codon 129 of the human prion protein (PrP) gene and the type (1 or 2) of protease-resistant PrP (PrP(res)) in the brain are major determinants of the clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). According to this molecular typing system, sCJD has been classified into six subgroups (MM1, MM2, MV1, MV2, VV1, and VV2). Besides these pure subgroups, mixed cases presenting mixed neuropathological phenotypes and more than one PrP(res) type have been found in sCJD. To investigate the frequency of the co-occurrence of types 1 and 2 PrP(res) in sCJD patients classified as MM1, we produced type 2 PrP(res)-specific antibody Tohoku 2 (T2) that can specifically detect the N-terminal cleavage site of type 2 PrP(res) after protease treatment and examined brain samples from 23 patients with sCJD-MM1. Western blot analysis using the T2 antibody revealed that the minority type 2 PrP(res) could be detected in all sCJD-MM1 brain samples including those of the cerebellum where sCJD-MM2 prions rarely accumulate. These results show that the co-occurrence of types 1 and 2 PrP(res) within a single sCJD-MM1 patient is a universal phenomenon. The general co-occurrence of multiple PrP(res) fragments within a single prion strain questions the validity of the conventional molecular typing system.

Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection

“…2, A and B) are in accord with WB observations obtained with more sensitive and specific antibodies that uncovered frequent, and probably ubiquitous, co-existence of 21-kDa (type 1) and 19-kDa (type 2) fragments of unglycosylated rPrP Sc in the same human prioninfected brain (17)(18)(19)(20)(21). Additionally, the growing body of evidence accumulated with sensitive conformational methods, including CDI, indicates extensive conformational heterogeneity of sCJD rPrP Sc fragments that otherwise show a single band (type) on WBs (5,(15)(16)(17).…”

“…Because the conformations of PrP Sc vary in different prion strains, the broad spectrum of distinct PrP Sc conformers recently found in different cases of sCJD using sensitive biophysical techniques implies that sCJD is caused by a broad array of distinct prions (5,15,16). Furthermore, the fre-quent, and perhaps universal, presence of both the 21-kDa (type 1) and 19-kDa (type 2) unglycosylated fragments of proteaseresistant (r) PrP Sc in sCJD (17)(18)(19)(20)(21) indicates the co-occurrence of markedly different PrP Sc conformers, often in the same anatomical structure in the same brain. Apart from challenging the validity of the clinicopathological classification of sCJD based on PRNP gene polymorphism and Western blot patterns of type 1 or type 2 rPrP Sc (14,22), these findings raise some fundamental questions.…”

Scientific Opinion on a request for a review of a scientific publication concerning the zoonotic potential of ovine scrapie prions

“…Res type have been found in sCJD (Kobayashi et al, 2011). The six sCJD types differ among each other in several clinical and histopathological features, and some of them propagate in animal models as distinct prion strains .…”

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

“…These quantitative findings extended previous qualitative observations with diverse antibodies and western blot techniques. [38][39][40][41][42] Apart from challenging the validity of the clinicopathological classification of sCJD based on PRNP gene polymorphism and western blot patterns of Type 1 or Type 2 rPrP Sc 24 , these findings raised some fundamental questions: (1) Do the coexistent Type 1 and Type 2 rPrP Sc form distinct or hybrid particles composed of both types of PrP Sc ? (2) What is the impact of coexistence of distinct PrP Sc conformers?…”