Related Experiment Videos
Scrapie-associated fibrils, PrP protein and the Sinc gene
Abstract:
Scrapie-associated fibrils (SAF) are disease-specific structures found in extracts of the brains of animals affected with scrapie. These structures are pathological aggregates of a normal host protein called PrP. In collaboration with Konrad Beyreuther (Heidelberg), we have characterized the multiple forms of PrP found in SAF fractions from mouse brain affected by the ME7 strain of scrapie. There is no in vivo N-terminal cleavage of the most abundant forms of PrP. However, N-terminal cleavage of some minor forms of PrP does occur in vivo within a domain of repetitive sequences at sites similar to but distinct from those cut by proteinase K in vitro. We suggest that such covalently modified forms of PrP may be the result of enzymic degradation occurring as a consequence rather than as a cause of disease. We also found a novel, as yet unidentified, amino acid derivative of the arginine residue at position 3 in both hamster and mouse PrP 33-35, which may predispose PrP to form SAF. Carlson and colleagues have discovered a linkage between the PrP gene and the murine gene provisionally called Prn-i which, from the work of Carp and coworkers, appears identical to the Sinc gene. The Sinc gene is the major gene determining the incubation period of all strains of scrapie in mice. We have evidence for a linkage of the PrP gene and Sinc using inbred mice of known Sinc genotype, including VM(Sincp7) and VM(Sincs7) congenic mice. PrP may even be the protein product of the Sinc gene.
Insights
Scrapie-associated fibrils (SAF) are linked to prion diseases. Researchers found modified forms of prion protein (PrP) and evidence suggesting the PrP gene is linked to the Sinc gene, which controls scrapie incubation periods in mice.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Scrapie-associated fibrils (SAF) are pathological aggregates of the host prion protein (PrP) found in scrapie-affected animal brains.
- Understanding PrP structure and genetic factors is crucial for prion disease research.
Purpose of the Study:
- To characterize different forms of PrP in SAF from scrapie-affected mouse brains.
- To investigate the in vivo cleavage of PrP and identify potential predisposing factors for SAF formation.
- To examine the genetic linkage between the PrP gene and the Sinc gene, which influences scrapie incubation periods.
Main Methods:
- Biochemical characterization of PrP forms in SAF fractions from ME7 scrapie strain-affected mouse brains.
- Analysis of in vivo N-terminal cleavage sites of PrP.
- Investigation of a novel amino acid derivative in PrP.
- Genetic linkage analysis using inbred mice with known Sinc genotypes.
Main Results:
- Identified multiple forms of PrP in SAF, with most abundant forms lacking in vivo N-terminal cleavage.
- Observed in vivo N-terminal cleavage in minor PrP forms at distinct sites.
- Discovered a novel amino acid derivative at arginine residue 3 in mouse and hamster PrP 33-35, potentially predisposing PrP to SAF formation.
- Provided evidence for linkage between the PrP gene and the Sinc gene in mice.
Conclusions:
- Covalently modified PrP forms may result from degradation post-disease onset.
- The novel PrP modification could be a factor in SAF formation.
- The PrP gene is likely linked to the Sinc gene, suggesting PrP might be the Sinc gene's protein product and play a role in regulating scrapie incubation times.