Physiopathology and molecular diagnosis for prion diseases

Prion diseases, including Creutzfeldt-Jakob disease (CJD), are infectious neurodegenerative disorders. The etiological agent, prion, is postulated to consist mainly of a proteinase K-resistant isoform of prion protein (PrPSc) which is generated by post-translational conversion from the proteinase K-sensitive normal version (PrPC) physiologically expressed on the surface of neuronal and glial cells. The constitutive conversion results in the tremendous accumulation of PrPSc in the prion-infected brain. Homozygous disruption of the Prnp gene encoding PrPC renders mice resistant to prion, and the animals are no longer capable of generating PrPSc, indicating an essential role for PrPSc in the pathogenesis of prion diseases. The PrP-null mice (Ngsk Prnp0/0) revealed progressive ataxia due to the degeneration of cellebellar Purkinje cells at old ages. Successful rescue of Ngsk Prnp0/0 mice from neurodegeneration by a transgene encoding the normal mouse PrPC has indicated that the functional loss of PrPC is essential for this phenotype. Moreover, we detected aberrant mRNAs chimeric between Prnp exon 1-2 and a novel gene encoding PrP-like protein (PrPLP). These results suggested that, in addition to the functional loss of PrPC, ectopic expression of the PrPLP in the brain of Ngsk Prnp0/0 mice could be associated with Purkinje cell degeneration.