Prion diseases (transmissible spongiform encephalopathies) are caused by conformational conversion of normal cellular prion protein (PrPC) to misfolded scrapie isoform (PrPSc). Which structural change defines the conversion from PrPC to PrPSc?
- A Cleavage of GPI anchor releasing PrPSc from cell surface
- B Increase in beta-sheet content from ~3% to ~43%, with corresponding decrease in alpha-helical content ✓
- C Glycosylation changes at Asn181 and Asn197 altering protein folding
- D Disulphide bond rearrangement converting two intramolecular bonds to intermolecular bonds
Explanation
The conformational conversion from PrPC to PrPSc involves a dramatic shift in secondary structure: PrPC has approximately 40% alpha-helix and only ~3% beta-sheet, while PrPSc has approximately 30% alpha-helix and 43% beta-sheet. This increased beta-sheet content makes PrPSc protease-resistant (PK-resistant), insoluble in detergents, and prone to amyloid fibril formation. The conversion is template-directed: PrPSc catalyses the refolding of normal PrPC in an autocatalytic chain reaction. Glycosylation changes affect strain typing but do not define the primary pathogenic conversion.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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