ABSTRACT
A hallmark in prion diseases is the conformational transition of the cellular prion protein (PrP(C)) into a pathogenic conformation, designated scrapie prion protein (PrP(Sc)), which is the essential constituent of infectious prions. Here, we show that epigallocatechin gallate (EGCG) and gallocatechin gallate, the main polyphenols in green tea, induce the transition of mature PrP(C) into a detergent-insoluble conformation distinct from PrP(Sc). The PrP conformer induced by EGCG was rapidly internalized from the plasma membrane and degraded in lysosomal compartments. Isothermal titration calorimetry studies revealed that EGCG directly interacts with PrP leading to the destabilizing of the native conformation and the formation of random coil structures. This activity was dependent on the gallate side chain and the three hydroxyl groups of the trihydroxyphenyl side chain. In scrapie-infected cells EGCG treatment was beneficial; formation of PrP(Sc) ceased. However, in uninfected cells EGCG interfered with the stress-protective activity of PrP(C). As a consequence, EGCG-treated cells showed enhanced vulnerability to stress conditions. Our study emphasizes the important role of PrP(C) to protect cells from stress and indicate efficient intracellular pathways to degrade non-native conformations of PrP(C).
Subject(s)
Drugs, Chinese Herbal/pharmacology , Flavonoids/pharmacology , Oxidative Stress/drug effects , Phenols/pharmacology , PrPC Proteins/drug effects , PrPSc Proteins/antagonists & inhibitors , Prion Diseases/drug therapy , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Catechin/analogs & derivatives , Catechin/metabolism , Catechin/pharmacology , Catechin/therapeutic use , Cell Death/drug effects , Cell Death/physiology , Cell Line, Tumor , Drugs, Chinese Herbal/metabolism , Drugs, Chinese Herbal/therapeutic use , Endocytosis/drug effects , Endocytosis/physiology , Flavonoids/metabolism , Flavonoids/therapeutic use , Humans , Lysosomes/drug effects , Lysosomes/metabolism , Mice , Molecular Structure , Oxidative Stress/physiology , Phenols/metabolism , Phenols/therapeutic use , Polyphenols , PrPC Proteins/metabolism , PrPSc Proteins/biosynthesis , Prion Diseases/metabolism , Prion Diseases/physiopathology , Protein Conformation/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology , SolubilityABSTRACT
Prion diseases are fatal and at present there are neither cures nor therapies available to delay disease onset or progression in humans. Inspired in part by therapeutic approaches in the fields of Alzheimer's disease and amyotrophic lateral sclerosis, we tested five different drugs, which are known to efficiently pass through the blood-brain barrier, in a murine prion model. Groups of intracerebrally prion-challenged mice were treated with the drugs curcumin, dapsone, ibuprofen, memantine and minocycline. Treatment with antibiotics dapsone and minocycline had no therapeutic benefit. Ibuprofen-treated mice showed severe adverse effects, which prevented assessment of therapeutic efficacy. Mice treated with low- but not high-dose curcumin and mice treated with memantine survived infections significantly longer than untreated controls (P<0.01). These results encourage further research efforts to improve the therapeutic effect of these drugs.