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

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 (PrPres) in the brain are major determinants of the clinico pathological 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 PrPres type have been found in sCJD. To investigate the frequency of the co-occurrence of types 1 and 2 PrPres in sCJD patients classified as MM1., we produced type 2 PrPres-specific antibody Tohoku 2 (T2) that can specifically detect the N-terminal cleavage site of type 2 PrPres 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 PrPres 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 PrPres within a single sCJD-MM1 patient is a universal phenomenon. The general co-occurrence of multiple PrPres fragments within a single prion strain questions the validity of the conventional molecular typing system. (Am J Pathol 2011, 178:1309-1315; DOI: 10.1016/j.ajpath.2010.11.069)