Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models.
Huntington's disease (HD) is a progressive neurodegenerative disorder for which only symptomatic treatments of limited effectiveness are available. Preventing early misfolding steps and thereby aggregation of the polyglutamine (polyQ)-containing protein huntingtin (htt) in neurons of patients may represent an attractive therapeutic strategy to postpone the onset and progression of HD. Here, we demonstrate that the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) potently inhibits the aggregation of mutant htt exon 1 protein in a dose-dependent manner. Dot-blot assays and atomic force microscopy studies revealed that EGCG modulates misfolding and oligomerization of mutant htt exon 1 protein in vitro, indicating that it interferes with very early events in the aggregation process. Also, EGCG significantly reduced polyQ-mediated htt protein aggregation and cytotoxicity in an yeast model of HD. When EGCG was fed to transgenic HD flies overexpressing a pathogenic htt exon 1 protein, photoreceptor degeneration and motor function improved. These results indicate that modulators of htt exon 1 misfolding and oligomerization like EGCG are likely to reduce polyQ-mediated toxicity in vivo. Our studies may provide the basis for the development of a novel pharmacotherapy for HD and related polyQ disorders.
Ehrnhoefer
Dagmar E
DE
Max Delbrueck Center for Molecular Medicine, Department of Neuroproteomics, Berlin, Germany.
Duennwald
Martin
M
Markovic
Phoebe
P
Wacker
Jennifer L
JL
Engemann
Sabine
S
Roark
Margaret
M
Legleiter
Justin
J
Marsh
J Lawrence
JL
Thompson
Leslie M
LM
Lindquist
Susan
S
Muchowski
Paul J
PJ
Wanker
Erich E
EE
D000818:Animals; D030801:Animals, Genetically Modified; D028241:Camellia sinensis / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000235:genetics; D005091:Exons; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D009046:Motor Neurons / Q000187:drug effects; D046912:Multiprotein Complexes; D009154:Mutation; D009410:Nerve Degeneration / Q000188:drug therapy; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D017956:Photoreceptor Cells, Invertebrate / Q000187:drug effects; D008517:Phytotherapy; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000187:drug effects / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D002392:Catechin; C045651:epigallocatechin gallate