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.
Highlights
Huntington’s disease (HD) is caused by an unstable CAG repeat expansion in the first exon of the IT-15 gene which encodes huntingtin, a 350 kDa protein, functionally involved in clathrin-mediated endocytosis, vesicle transport processes and transcriptional regulation [1,2]
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
We found that the yeast cells, after removal of the compound, do not grow on SD þ Gal plates, whereas they can grow on SD þ Glu medium
Summary
Huntington’s disease (HD) is caused by an unstable CAG repeat expansion in the first exon of the IT-15 gene which encodes huntingtin (htt), a 350 kDa protein, functionally involved in clathrin-mediated endocytosis, vesicle transport processes and transcriptional regulation [1,2]. The disorder is characterized by a progressive loss of cortical and striatal neurons and the formation of neuronal inclusions containing aggregated htt protein [4,5]. There is evidence that mutant htt aggregate formation is causally linked to the progressive neuropathology of the disease [6], though it is not clear whether large insoluble, fibrillar structures or smaller assemblies of htt are the toxic agents responsible for neuronal damage and loss [reviewed by [7]]. Toxicity could arise from the recruitment of other polyQ-containing proteins, i.e. transcription factors or wildtype htt, into the neuronal inclusions, which would result in a loss of their normal cellular functions [see review by [8]].
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