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Scrapie-associated PrP accumulation and its inhibition: revisiting the amyloid-glycosaminoglycan connection
1Laboratory of Persistent Viral Diseases, NIH Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, Hamilton, Montana 59840.
Abstract:
An abnormal protease-resistant isoform of the protein PrP accumulates in the brain of hosts with transmissible spongiform encephalopathies (TSEs) and appears to be centrally involved in TSE pathogenesis. Studies with scrapie-infected tissue culture cells have indicated that this abnormal PrP is formed from an apparently normal precursor on the plasma membrane or along an endocytic pathway to the lysosomes. Inhibitors of protease-resistant PrP accumulation might serve as tools for studying the basic mechanism of protease-resistant PrP formation and as potential drugs for TSE therapy. Using scrapie-infected neuroblastoma cells to screen for such compounds in vitro, we found that the amyloid binding dye Congo red and certain sulfated glycans potently inhibited the accumulation of protease-resistant PrP in scrapie-infected cells without apparent effects on the metabolism of the normal isoform. The relative potencies of the sulfated glycans corresponded with their previously determined anti-scrapie activities in vivo, suggesting that the prophylactic effects of sulfated polyanions may be due to inhibition of protease-resistant PrP accumulation. Since protease-resistant PrP amyloid is known to contain sulfated glycosaminoglycans, as do other naturally derived amyloids, we hypothesize that these sulfated inhibitors competitively block binding between PrP and endogenous glycosaminoglycans that is important for its accumulation in a protease-resistant, potentially amyloidogenic state. Drugs which interfere with this (pre)amyloid-glycosaminoglycan interaction may be useful for treating a variety of amyloidoses.
Insights
Certain sulfated glycans and Congo red inhibit abnormal prion protein (PrP) accumulation in transmissible spongiform encephalopathies (TSEs). This suggests a therapeutic strategy targeting PrP-glycosaminoglycan interactions for TSEs and other amyloidoses.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Transmissible spongiform encephalopathies (TSEs) are linked to abnormal protease-resistant prion protein (PrP) accumulation in the brain.
- PrPSc is thought to form from a normal precursor (PrPC) on the cell surface or via endocytosis.
- Inhibiting PrPSc formation is a key target for TSE therapy and understanding pathogenesis.
Purpose of the Study:
- To screen for compounds that inhibit the accumulation of protease-resistant PrP in scrapie-infected cells.
- To investigate the potential of these compounds as therapeutic agents for TSEs.
- To elucidate the mechanism by which sulfated glycans inhibit PrPSc formation.
Main Methods:
- Utilized scrapie-infected neuroblastoma cells for in vitro screening.
- Assayed inhibition of protease-resistant PrP accumulation.
- Correlated in vitro findings with in vivo anti-scrapie activities of sulfated glycans.
Main Results:
- Congo red and specific sulfated glycans potently inhibited protease-resistant PrP accumulation in infected cells.
- These inhibitors did not affect the metabolism of the normal PrP isoform.
- The efficacy of sulfated glycans in vitro correlated with their known in vivo anti-scrapie activity.
Conclusions:
- Sulfated glycans and Congo red show promise for inhibiting PrPSc accumulation.
- The mechanism likely involves competitive inhibition of PrP binding to endogenous glycosaminoglycans.
- Targeting (pre)amyloid-glycosaminoglycan interactions may offer a therapeutic strategy for TSEs and other amyloidoses.