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Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Post-translational changes to PrP alter transmissible spongiform encephalopathy strain properties
Enrico Cancellotti1, Sukhvir P Mahal, Robert Somerville
1Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, UK.
The EMBO Journal
|February 12, 2013
Summary
Altering the glycosylation of prion protein (PrP) can change the characteristics of transmissible spongiform encephalopathy (TSE) strains. This suggests post-translational modifications influence prion disease strain properties.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Transmissible spongiform encephalopathies (TSEs) are prion diseases caused by abnormal prion protein (PrPSc) conformers.
- TSE strains exhibit distinct phenotypic properties despite sharing the same amino acid sequence for PrPSc.
- Post-translational modifications of PrP are hypothesized to encode strain-specific information.
Purpose of the Study:
- To investigate the impact of host prion protein (PrP) glycosylation status on TSE strain characteristics.
- To determine if altering N-glycosylation sites of PrP affects the infectious properties of TSE strains.
Main Methods:
- Inoculation of wild-type mice with TSE strains passaged through transgenic mice lacking N-glycosylation sites on PrP.
- Comparison of emergent TSE isolates with wild-type passaged strains using in vivo strain typing.
- In vitro analysis using the standard scrapie cell assay to assess infectious properties.
Main Results:
- Strain-specific characteristics of the 79A TSE strain were altered when PrPSc lacked one or both N-glycans.
- Changes in PrP glycosylation resulted in modified infectious properties of the TSE strains.
- The study provides evidence that post-translational modifications can select for mutant TSE strains.
Conclusions:
- Host PrP glycosylation status significantly influences TSE strain characteristics.
- Post-translational modifications of PrP are critical determinants of prion strain diversity.
- Altered glycosylation can lead to the emergence of novel or altered TSE strains.
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