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Molecular classification of sporadic Creutzfeldt-Jakob disease
Andrew F Hill1, Susan Joiner, Jonathan D F Wadsworth
1MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.
Abstract:
According to the protein-only hypothesis of prion propagation, an abnormal isoform (designated PrP(Sc)) of the cellular prion protein (PrP(C)) is the principal or sole component of transmissible prions. However, the existence of multiple prion strains has been difficult to accommodate within this hypothesis. We have previously reported the identification of four types of human PrP(Sc) associated with sporadic and acquired human prion diseases. These PrP(Sc) types are distinguished by differing molecular mass of fragments following limited proteinase K digestion and by differing ratios of di-, mono- and unglycosylated PrP(Sc). That these discrete biochemical features of PrP(Sc) are serially transmissible to human PrP in transgenic mice following experimental transmission suggests that they may be responsible for encoding prion strain diversity. Here we present detailed clinical, pathological and molecular data from a large number of sporadic Creutzfeldt-Jakob disease (CJD) cases. We show that PrP(Sc) types are associated with codon 129 status, duration of illness and neuropathological phenotype. A novel PrP(Sc) type is presented, illustrating further heterogeneity in CJD, and suggesting that further molecular subtypes of CJD may exist at lower frequencies. A molecular classification of sporadic CJD is proposed.
Insights
The protein-only hypothesis struggles with prion strain diversity. This study links specific abnormal prion protein (PrPSc) types to Creutzfeldt-Jakob disease subtypes, suggesting PrPSc biochemical features encode strain diversity.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- The protein-only hypothesis posits abnormal prion protein (PrPSc) as the sole component of prions.
- Accommodating prion strain diversity within this hypothesis remains a challenge.
- Previous work identified four human PrPSc types associated with prion diseases.
Purpose of the Study:
- To investigate the association between PrPSc types and sporadic Creutzfeldt-Jakob disease (CJD) characteristics.
- To explore the role of PrPSc biochemical features in encoding prion strain diversity.
- To propose a molecular classification for sporadic CJD.
Main Methods:
- Analysis of clinical, pathological, and molecular data from a large cohort of sporadic CJD cases.
- Characterization of PrPSc types based on proteinase K digestion fragment mass and glycosylation ratios.
- Experimental transmission studies in transgenic mice to assess PrPSc transmissibility and strain encoding.
Main Results:
- PrPSc types correlate with codon 129 genotype, illness duration, and neuropathological phenotype in sporadic CJD.
- A novel PrPSc type was identified, revealing further heterogeneity in CJD.
- Biochemical features of PrPSc are serially transmissible, supporting their role in strain diversity.
Conclusions:
- Prion strain diversity may be encoded by the distinct biochemical features of abnormal prion protein (PrPSc).
- Sporadic CJD exhibits molecular heterogeneity, with PrPSc types linked to clinical and pathological phenotypes.
- A molecular classification of sporadic CJD based on PrPSc types is proposed.