Scrapie associated PrP accumulation and its prevention: insights from cell culture

Transmissible spongiform encephalopathies (TSEs), Alzheimer's disease and other amyloidoses result in the accumulation of abnormally stable, potentially amyloidogenic proteins that appear to play central roles in disease pathogenesis. Scrapie-infected tissue culture cells have become well-developed models for studying how the TSE-specific protein, protease-resistant PrP, is made from its apparently normal precursor. The conversion of PrP to the protease-resistant state occurs on the plasma membrane or along an endocytic pathway to the lysosomes. The protease-resistant PrP has a much longer half-life than normal PrP and its accumulation in lysosomes may feature in TSE pathogenesis. Congo red and certain sulfated glycans potently inhibit protease-resistant PrP formation or stabilization in cell culture. These and other observations suggest that an interaction of PrP with glycosaminoglycans is critical in protease-resistant PrP accumulation and raises the possibility that therapeutic strategies for TSEs and other amyloidoses could be based on blocking (pre)amyloid-glycosaminoglycan interactions.