title: Classification of sporadic Creutzfeldt-Jakob disease revisited.
abstract: 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 (PrP(Sc)), 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 PrP(Sc) molecular mass under the conditions that allowed wide variability of the pH of the PrP(Sc) preparations as well as under stringent pH conditions, using high-resolution gel electrophoresis. We also compared the characteristics of the PrP(Sc) 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 PrP(Sc) molecular mass did not differ between short- and long-duration sCJDMM1 subjects. The conformational characteristics of the protease-resistant PrP(Sc) 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 PrP(Sc) 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 PrP(Sc) characteristics. These data indicate that the differentiation of sCJDMM1 into two subgroups is not currently justified.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Cali
authors.forename: Rudolph
authors.initials: R
authors.lastname: Castellani
authors.forename: Jue
authors.initials: J
authors.lastname: Yuan
authors.forename: Amer
authors.initials: A
authors.lastname: Al-Shekhlee
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.forename: Xiangzhu
authors.initials: X
authors.lastname: Xiao
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Moleres
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
mesh_terms: D000368:Aged; D015153:Blotting, Western / Q000379:methods; D001923:Brain Chemistry; D002498:Centrifugation / Q000379:methods; D002614:Chelating Agents / Q000494:pharmacology; D007562:Creutzfeldt-Jakob Syndrome / Q000145:classification* / Q000473:pathology; D004492:Edetic Acid / Q000494:pharmacology; D019286:Endopeptidase K / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007118:Immunoassay / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D010641:Phenotype; D018620:PrPSc Proteins / Q000737:chemistry*; D011487:Protein Conformation; D013395:Sucrose; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D002614:Chelating Agents; D018620:PrPSc Proteins; D013395:Sucrose; D004492:Edetic Acid; D019286:Endopeptidase K