Green tea (−)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models

TLDR

Huntington's disease is a progressive neurodegenerative disorder with limited symptomatic treatments, and preventing early misfolding and aggregation of mutant huntingtin protein is a promising therapeutic strategy. The study aims to evaluate whether the green tea polyphenol EGCG can modulate early misfolding of mutant huntingtin and reduce toxicity, providing a basis for novel HD therapies. Dot‑blot assays and atomic force microscopy revealed that EGCG interferes with very early misfolding and oligomerization of mutant htt exon 1 protein in vitro. EGCG potently inhibits mutant huntingtin aggregation in a dose‑dependent manner, reduces aggregation and cytotoxicity in yeast, improves photoreceptor degeneration and motor function in HD flies, and overall suggests that modulating early misfolding events can diminish polyQ‑mediated toxicity in vivo.

Abstract

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.