A 65-year-old man presents with rapidly progressive dementia, myoclonus, visual hallucinations, and cerebellar ataxia over 6 weeks. CSF 14-3-3 protein is positive; MRI DWI shows cortical ribboning and basal ganglia signal change. Autopsy shows spongiform change (vacuolation of the neuropil), neuronal loss, gliosis, and PrP immunostaining. Which of the following best explains the molecular basis of neurodegeneration in this disease?

• A The prion protein PrPSc triggers a caspase-1-dependent pyroptotic pathway in neurons by forming a pore in the plasma membrane
• B PrPSc activates the complement membrane attack complex on neurons via GPI-anchor-mediated C1q binding, causing direct complement-driven neuronal lysis
• C PrPSc acts as a template that binds and conformationally converts normal PrPC (predominantly alpha-helical, GPI-anchored) into beta-sheet-rich PrPSc; accumulation of PrPSc as insoluble aggregates in neurons and neuronal processes causes synaptic dysfunction, UPS overload, ER stress, and autophagy failure, leading to spongiform vacuolation and neuronal death ✓
• D PrPSc causes mitochondrial dysfunction by sequestering cytochrome c in amyloid plaques, impairing electron transport chain and causing bioenergetic failure

Explanation

Prion diseases (CJD in this case) are caused by conformational conversion of the normal cellular prion protein PrPC (predominantly alpha-helical, protease-sensitive, GPI-anchored) into the abnormal PrPSc isoform (predominantly beta-sheet, protease-resistant). PrPSc acts as an infectious template (protein-only hypothesis), catalyzing the conversion of PrPC to PrPSc without nucleic acid involvement. Accumulating PrPSc cannot be cleared by the UPS or autophagy (protease-resistant), leading to progressive synaptic dysfunction, ER stress, mitochondrial compromise, and ultimately spongiform change (vacuolation of neuronal soma and neuropil) and neuronal dropout without inflammatory infiltrate. Myoclonus is attributed to cortical hyperexcitability from synaptic protein loss.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.