A 55-year-old man presents with a rapidly progressive dementia, myoclonus, and cerebellar ataxia over 8 months. EEG shows periodic sharp wave complexes. Brain biopsy (not typically done antemortem) would show spongiform vacuolation without inflammation and PrP immunopositivity. What is the mechanism of pathogenesis in prion disease?

• A PrP gene mutation creates a frameshifted protein that activates autophagy and neuronal death
• B PrPsc directly activates caspase-12 via endoplasmic reticulum stress in neurons
• C Normal PrPc is converted to misfolded PrPsc by conformational templating; PrPsc accumulates and is resistant to proteolytic degradation ✓
• D Prion protein acquires a viral RNA genome that replicates in neurons causing cytopathic effect

Explanation

Prion diseases are caused by the conformational conversion of the normal, predominantly alpha-helical PrPc (cellular prion protein) to an abnormal, beta-sheet-rich isoform PrPsc (scrapie form). PrPsc acts as a template that induces conformational change in PrPc, amplifying misfolded protein. PrPsc is protease-resistant, accumulates in neurons, and causes spongiform vacuolation and neuronal death by poorly understood mechanisms. The absence of inflammatory response and the purely conformational (non-nucleic acid) nature make prions unique infectious agents.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.