NR ATGM
AU Parchi,P.
TI Molecular heterogeneity in human TSEs: PrP27-30 typing and beyond
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-43
PT Konferenz-Vortrag
AB The discovery that the clinico-pathological heterogeneity of Creutzfeldt-Jakob disease (CJD) largely correlates at the molecular level with the genotype at codon 129 (MM, MV, VV) and either one of two major types of PrP27-30 with distinct physicochemical properties (types 1 and 2) has provided the basis for a molecular classification of CJD, and a potentially powerful method for strain typing. Despite the significant advance, however, additional work needs to be to done to fully explore the issue of the molecular basis of phenotypic variability and strain diversity in CJD. Evidence indicates that part of the observed heterogeneity of PrP27-30 may simply result from varying experimental conditions. Furthermore, it is still unknown whether a specific PrP27-30 type may be linked to each CJD phenotypic variant. Lastly, the recent identification of novel C-terminal fragments of PrP has provided a potential novel molecular marker, but it is currently unclear to what extent it is related to the CJD phenotype. We further analyzed PrP 27-30 properties using a high resolution gel electrophoresis system and varying experimental conditions and found that pH varies among CJD brain homogenates in standard buffers thereby influencing the characteristics of PrP 27-30. We also found that PrP 27-30 types 1 and 2 are heterogeneous species, which can be further distinguished into molecular subtypes that largely fit the current histopathologic classification of CJD variants. By means of a novel antibody that, in contrast to 3F4, recognizes an epitope located outside the primary cleavage site of PrP27-30 type 2, we demonstrated that all type 2 CJD subtypes include an additional PrP27-30 conformer. Finally, our latest results indicate that the physico-chemical heterogeneity of CJD associated PrP27-30 extends to abnormal truncated forms of the protein and that their characterization is also useful for the molecular diagnosis of some CJD subtypes.
AD P.Parchi, Laboratory of Neuropathology, Department of Neurological Sciences, University of Bologna, Italy
SP englisch
PO Deutschland