Aetiology and pathogenesis

CJD is caused by the intracellular deposition of an abnormal form of the normal cellular prion protein. This abnormal form of prion protein, designated PrPsc, is insoluble and proteinase resistant and can be identified with immunocytochemistry on pathological specimens. PrPsc differs from the normal soluble human prion protein, PrPc, not by its sequence of amino acids but by the conformation in which the protein is formed. The PrP gene has been identified, but as yet its normal function is unknown. PrP-knockout transgenic mice develop normally.

The precipitation of PrPsc spreads within the central nervous system because of the ability of PrPsc to catalyse the conversion of endogenous PrPc to PrPsc.

The protein-only, or prion, theory of can explain the three observed natural histories of the spongiform encephalopathies:

• sporadic:
  • conversion of PrPc to PrPsc may occur as a random event
    
    
• familial:
  • specific PrP mutations make random conversions from PrPc to PrPsc more likely
    
    
• acquired:
  • iatrogenic or environmental exposure to PrPsc may trigger endogenous production of PrPsc