Classification of sporadic Creutzfeldt–Jakob disease revisited
1 Department of Pathology, Case Western Reserve University Cleveland, OH, USA 2 Department of Neurology, Case Western Reserve University Cleveland, OH, USA 3 Division of Neuropathology, Department of Pathology University of Maryland, Baltimore, MD, USA 4 Dipartimento di Scienze Neurologiche, Università di Bologna Bologna, Italy
Correspondence to: Drs Pierluigi Gambetti or Wen-Quan Zou, Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA E-mail: pxg13{at}case.edu and wenquan.zou{at}case.edu
The sporadic form of Creutzfeldt–Jakob disease (sCJD) has been classified on the basis of the molecular mass of the protease-resistant scrapie prion protein (PrPSc), which can be type 1 or type 2, and the genotype at the methionine (M)/valine (V) polymorphic codon 129, which can be MM, MV or VV. In one classification proposed by Parchi et al., [Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I , Budka H , Kopp N , Piccardo P , Poser S , Rojiani A , Streichemberger N , Julien J , Vital C , Ghetti B , Gambetti P , Kretzschmar H . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224–33.] the most common subtype of sCJD, designated sCJDMM1, is viewed as a single entity. Two other classifications proposed by Collinge et al. [Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 1996; 383: 685–90.] and Zanusso et al., [Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S . pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377–80.] respectively, subdivide sCJDMM1 into two subtypes on the basis of the different molecular mass and phenotypic characteristics, primarily disease duration. To resolve this discrepancy, we divided a group of 22 subjects with confirmed sCJDMM1 according to Parchi et al. into two sub-populations according to whether the disease duration was <5 months (short-duration subjects) or >7 months (long-duration subjects). We then examined the PrPSc molecular mass under the conditions that allowed wide variability of the pH of the PrPSc preparations as well as under stringent pH conditions, using high-resolution gel electrophoresis. We also compared the characteristics of the PrPSc associated with the short- and long-duration subjects using two-dimensional immunoblot, conformational stability immunoassay and sucrose gradient fractionation. Finally, the two sub-populations were also compared with regard to their clinical and pathological features including the lesion profiles. When sample homogenization and protease digestion were performed under stringent pH conditions, the PrPSc molecular mass did not differ between short- and long-duration sCJDMM1 subjects. The conformational characteristics of the protease-resistant PrPSc as well as the clinical and pathological phenotypes were also homogeneous except for the more severe lesions of the long-duration cases. We therefore conclude that the variability of the PrPSc molecular mass underlying the division of sCJDMM1 into two subtypes is largely due to pH variations during tissue preparation, and sCJDMM1 with short and long disease duration have similar phenotypes and PrPSc characteristics. These data indicate that the differentiation of sCJDMM1 into two subgroups is not currently justified.
Key Words: classification; disease duration; prion disease; prion protein; Sporadic Creutzfeldt-Jakob disease
Abbreviations: CSI, conformational stability immunoassay; EDTA, ethylenediamine tetra-acetic acid; GdnHCl, guanidine hydrochloride; mAb, monoclonal antibody; PBS, phosphate-buffered saline; PK, proteinase K; PrPSc, scrapie prion protein; sCJD, sporadic Creutzfeldt–Jakob disease; SDS, sodium dodecyl sulphate; TH, total homogenates
Received April 12, 2006. Revised July 19, 2006. Accepted July 25, 2006.
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