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

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

Role of heat shock proteins during polyglutamine neurodegeneration: mechanisms and hypothesis

A common feature of many neurodegenerative diseases, including Alzheimer's and Parkinsons's disease, the prion disorders, and the CAG repeat polyglutamine (polyQ) diseases, is the occurrence of protein aggregates within or outside of nerve cells. Molecular chaperones such as heat shock proteins (HSPs) have been proposed to play a critical role in preventing the accumulation of misfolded proteins that lead to the deposition of aggregates during pathology. This article focuses on the role of HSPs during polyQ pathologies, which include Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral and pallidoluysian atrophy, and several forms of spinocerebellar ataxia. Recently, unifying mechanisms that are involved during polyQ disease have emerged, such as abnormal transcription, impaired degradation systems, and interference of a polyQ expansion with neuronal survival and death-signaling pathways like the activation of caspases and kinases. This article reviews recent studies that point to the involvement of these mechanisms during polyQ pathology and discusses how HSPs can interfere with such processes by paying special attention to HSPs as modulators of survival and death-signaling pathways

Selective and compartmentalized myelin expression of HspB5

In the present study, we reveal myelin specific expression and targeting of mRNA and biochemical pools of HspB5 in the mouse CNS. Our observations are based on in-situ hybridisation, electron microscopy and co-localisation with 2’,3’-Cyclin-Nucleotide 3’-Phosphodiesterase (CNPase), reinforcing this myelin selective expression. HspB5 mRNA might be targeted to these structures based on its presence in discrete clusters resembling RNA granules and the presence of a putative RNA transport signal. Further, sub-cellular fractionation of myelin membranes reveals a distinct sub-compartment specific association and detergent solubility of HspB5. This is akin to other abundant myelin proteins and is consistent with HspB5’s association with cytoskeletal/membrane assemblies. Oligodendrocytes have a pivotal role in supporting axonal function via generating and segregating the ensheathing myelin. This specialisation places extreme structural and metabolic demands on this glial cell type. Our observations place HspB5 in oligodendrocytes which may require selective and specific chaperone capabilities to maintain normal function and neuronal support