Green tea extracts interfere with the stress-protective activity of PrP and the formation of PrP.
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).
Rambold
Angelika S
AS
Department of Biochemistry, Neurobiochemistry, Ludwig-Maximilians-Universität München, München, Germany.
Miesbauer
Margit
M
Olschewski
Diana
D
Seidel
Ralf
R
Riemer
Constanze
C
Smale
Lindsay
L
Brumm
Lisa
L
Levy
Michal
M
Gazit
Ehud
E
Oesterhelt
Dieter
D
Baier
Michael
M
Becker
Christian F W
CF
Engelhard
Martin
M
Winklhofer
Konstanze F
KF
Tatzelt
Jörg
J
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002392:Catechin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D059808:Polyphenols; D018621:PrPC Proteins / Q000187:drug effects* / Q000378:metabolism; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011487:Protein Conformation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012995:Solubility
D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D018621:PrPC Proteins; D018620:PrPSc Proteins; C417940:gallocatechin gallate; D002392:Catechin; C045651:epigallocatechin gallate