Metallothioneins and copper metabolism are candidate therapeutic targets in Huntington's disease

Sarah L Hands,Flaviano Giorgini,Robert Mason,M Umar Sajjad,Andreas Wyttenbach

doi:10.1042/bst0380552

Sarah L Hands, Flaviano Giorgini + Show 3 more

Open Access

https://doi.org/10.1042/bst0380552

Copy DOI

Abstract

HD (Huntington's disease) is caused by a polyQ (polyglutamine) expansion in the huntingtin protein, which leads to protein misfolding and aggregation of this protein. Abnormal copper accumulation in the HD brain was first reported more than 15 years ago. Recent findings show that copper-regulatory genes are induced during HD and copper binds to an N-terminal fragment of huntingtin, supporting the involvement of abnormal copper metabolism in HD. We have demonstrated that in vitro copper accelerates the fibrillization of an N-terminal fragment of huntingtin with an expanded polyQ stretch (httExon1). As we found that copper also increases polyQ aggregation and toxicity in mammalian cells expressing httExon1, we investigated further whether overexpression of genes involved in copper metabolism, notably MTs (metallothioneins) known to bind copper, protect against httExon1 toxicity. Using a yeast model of HD, we have shown that overexpression of several genes involved in copper metabolism reduces polyQ-mediated toxicity. Overexpression of MT-3 in mammalian cells significantly reduced polyQ aggregation and toxicity. We propose that copper-binding and/or -chaperoning proteins, especially MTs, are potential therapeutic targets for HD.

Highlights

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal polyglutamine expansion in the 350kDa protein, huntingtin
Due to the observed effect of copper on aggregation of httEx1 protein in vitro, we hypothesised that alterations in copper metabolism would affect aggregation and toxicity induced by expression of httEx1 in vivo
Our results show that altering levels of copper either by addition of exogenous copper, addition of a copper chelator or over-expression of copper homeostatic genes affects aggregation and/or toxicity of an aggregation-prone N-terminal fragment of htt

Summary

Introduction

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in the 350kDa protein, huntingtin (htt). Many cellular dysfunctions have been identified that could participate in the disease process including impaired transcription, mitochondrial abnormalities, dysregulation of the cellular redoxhomeostasis and deficits in protein degradation pathways, axonal transport and synaptic function (for a recent review see [2]) Both iron and copper accumulate in the central nervous system (CNS) of HD mouse models and in the HD brain [3, 4] and could play a role in the above-mentioned cellular alterations that occur in HD. By examining published gene expression data from HD cell and mouse models and human HD brain tissue we found that copper-binding/chaperoning proteins, including metallothioneins (MTs), were consistently up-regulated (Table 1) This could reflect a protective response against increased copper and ROS and/or a disruption of copper homeostasis more generally. Because oligomerisation and the production of amyloid-like structures of Nterminal htt has been tightly linked to cellular toxicity [8-11] we have investigated whether copper modulates the formation of such protein assemblies using atomic force microscopy and biochemical assays and tested if increased expression of copper-binding proteins reduces htt aggregation

Methods

Results

Conclusion