Molecular Pathology of Human Prion Diseases

Author: P. Parchi
Submitted: Wednesday 8th of September 2010 08:47:52 AM
Submitted by: egf
Educational levels: expert, qc1, qc2, qc3



At variance with the most common neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease prion diseases comprise a broad spectrum of clinico- pathological variants. These disease subtypes significantly differ in disease duration, symptoms at onset, relative severity and distribution of brain lesions such as spongiosis, neuronal loss, and gliosis, as well as presence and morphology of amyloid plaques. Different prion strains are believed to be the main cause of phenotypic diversity in prion diseases. Prion strains were originally defined by their distinct disease phenotypes upon transmission to syngenic animals, which persist on serial transmission. In addition, the host genotype variability in the gene encoding the cellular prion protein, PrPC (PRNP), has also been recognized as a causal factor for phenotypic heterogeneity. Much progress has been made in understanding the molecular basis of prion strains and phenotypic variability in the last 15 years. The focus at molecular level has been the characterization of the physicochemical properties of PrPSc, which according to the protein-only hypothesis enciphers the strain-specific properties in its conformation. Distinct PrPSc profiles or types characterized by specific physicochemical properties such as size after protease treatment, degree of protease resistance or conformational stability and glycoform ratio have been found in both humans and animals. In humans, two major human PrPSc types are known, which have been extensively reproduced among laboratories: type 1 with a relative molecular mass of 21 kDa and the primary cleavage site at residue 82 and type 2 with relative molecular mass of 19 kDa and the primary cleavage site at residue 97. The two PrPTSE types in conjunction with the codon 129 genotype have largely explained the phenotypic variability of human sporadic prion disease and have provided a molecular basis for disease classification (i.e. MM1, MM2, VV1 etc.). More recent issues that have been addressed include the description and characterization of CJD cases with mixed type 1 and type 2 features, the definition of the phenotypic and molecular spectrum of atypical cases not fitting the current classification and showing unusual PrPSc properties, and the study of the extent of phenotypic overlap between sporadic and genetic CJD. We contributed to these issues by studying systematically the clinico-pathogical and molecular phenotypes in a large cohort of cases including about 300 cases of sporadic prion disease and more than 100 genetic CJD cases. Among them we found 5 cases with atypical features. Furthermore, PrPSc types 1 and 2 co-occurrence was detected in about one third sCJD cases and was higher in MM than in MV or VV subjects. All subjects with coexisting PrPSc types shared clinical and histopathological features with the previously described sCJD phenotypes. The relative amount of PrPSc types 1 and 2 affected both histopathological and clinical features such as the duration of clinical disease and the symptoms at onset. The deposition of either type 1 or 2, when concurrent, was not random and indicated that a sensitive identification and classification of such cases require the assessment of critical brain regions. Finally, the study of genetic cases suggests that the phenotypic variability of genetic CJD largely reproduces that of sCJD As in sCJD, the codon 129 genotype and the physicochemical properties of PrPSc largely specify phenotypic variability, whereas the most common mutations linked to CJD appear to have a variable, and, overall, less significant effect on disease phenotype and apparently do not determine strain-specific properties.


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P. Parchi. Molecular Pathology of Human Prion Diseases. EUROGENE portal. September 2010. online:



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