Brain Advance Access originally published online on September 4, 2009
Brain 2009 132(10):2643-2658; doi:10.1093/brain/awp196
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt–Jakob disease: its effect on the phenotype and prion-type characteristics
1 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA 2 Division of Neuropathology, Department of Pathology, University of Maryland, Baltimore, MD 21201, USA 3 Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA 4 Central Veterinary Institute of Wageningen UR, NL-8203 AA 2004, Lelystad, The Netherlands 5 Dipartimento di Scienze Neurologiche, Università di Bologna, 40123 Bologna, Italy
Correspondence to: Dr Pierluigi Gambetti, Department of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA E-mail: pxg13{at}case.edu Correspondence may also be addressed to: Dr Wen-Quan Zou, E-mail: wenquan.zou{at}case.edu
Five phenotypically distinct subtypes have been identified in sporadic Creutzfeldt–Jakob disease (sCJD), based on the methionine/valine polymorphic genotype of codon 129 of the prion protein (PrP) gene and the presence of either one of the two protease K-resistant scrapie prion protein (PrPSc) types identified as 1 and 2. The infrequent co-existence of both PrPSc types in the same case has been known for a long time. Recently, it has been reported, using type-specific antibodies, that the PrPSc type 1 is present in all cases of sCJD carrying PrPSc type 2. The consistent co-occurrence of both PrPSc types complicates the diagnosis and the current classification of sCJD, and has implications for the pathogenesis of naturally occurring prion diseases. In the present study, we investigated the prevalence of PrPSc types 1 and 2 co-occurrence, along with its effects on the disease phenotype and PrPSc strain characteristics, comparatively analysing 34 cases of sCJD, all methionine homozygous at codon 129 of the PrP gene (sCJDMM). To minimize overestimating the prevalence of the sCJDMM cases carrying PrPSc types 1 and 2 (sCJDMM1-2), we used proteinase K concentrations designed to hydrolyse all fragments resulting from an incomplete digestion, while preserving the protease-resistant PrPSc core. Furthermore, we used several antibodies to maximize the detection of both PrPSc types. Our data show that sCJDMM cases associated exclusively with either PrPSc type 1 (sCJDMM1) or PrPSc type 2 (sCJDMM2) do exist; we estimate that they account for approximately 56% and 5% of all the sCJDMM cases, respectively; while in 39% of the cases, both PrPSc types 1 and 2 are present together (sCJDMM1-2) either mixed in the same anatomical region or separate in different regions. Clinically, sCJDMM1-2 had an average disease duration intermediate between the other two sCJDMM subtypes. The histopathology was also intermediate, except for the cerebellum where it resembled that of sCJDMM1. These features, along with the PrP immunostaining pattern, offer a diagnostic clue. We also observed a correlation between the disease duration and the prevalence of PrPSc type 2 and sCJDMM2 phenotypes. The use of different antibodies and of the conformational stability immunoassay indicated that the co-existence of types 1 and 2 in the same anatomical region may confer special conformational characteristics to PrPSc types 1 and 2. All of these findings indicate that sCJDMM1-2 should be considered as a separate entity at this time.
Key Words: prion protein; prion disease; co-existence; conformation; sporadic Creutzfeldt–Jakob disease
Abbreviations: CSI, conformational stability immunoassay; mAb, monoclonal antibodies; MM, homozygous methionine; MV, heterozygous methionine/valine; NPDPSC, National Prion Disease Pathology Surveillance Centre; PK, proteinase K; PrP, prion protein; sCJD, sporadic Creutzfeldt–Jakob disease; VV, homozygous valine
Received February 18, 2009. Revised May 16, 2009. Accepted June 8, 2009.