A patient develops rapidly progressive dementia with myoclonus and periodic sharp-wave complexes on EEG. CSF real-time quaking-induced conversion (RT-QuIC) assay is positive. Neuropathological examination shows spongiform change in the cortex, neuronal loss, and astrogliosis without inflammatory infiltrate. This is Creutzfeldt-Jakob disease (CJD). The fundamental molecular mechanism is:
- A Conformational conversion of normal cellular prion protein (PrPC, alpha-helical) to misfolded disease form (PrPSc, beta-sheet-rich) that propagates by inducing conversion of further PrPC molecules ✓
- B Loss of normal PrPC function due to PRNP nonsense mutation causing neurodegeneration
- C Viral-induced PrP gene amplification causing toxic PrP overexpression
- D Autoimmune T-cell attack on PrPC-expressing neurons causing apoptosis
Explanation
The protein-only (prion) hypothesis: pathogenic prion disease is caused by PrPSc (scrapie isoform) — a misfolded, protease-resistant, beta-sheet-rich conformer of the normal cellular prion protein PrPC (alpha-helical, protease-sensitive). PrPSc acts as a template inducing PrPC to adopt the PrPSc conformation in a self-perpetuating chain reaction. This propagates exponentially without nucleic acid, explaining transmissibility. Accumulation of PrPSc causes spongiform vacuolation, neuronal death (via multiple mechanisms including UPR activation), and astrogliosis. RT-QuIC detects the seeding activity of PrPSc in CSF with high sensitivity/specificity for sporadic CJD.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.