Studies On The Mechanism Of Copper’s Effect On Huntington’s Disease

Huntington’s disease(HD) is a progressive neurodegenerative disorder, which is characterized by movement disorder, psychiatric symptoms, and cognitive dysfunction. Eeffective treatments to slow down or to stop the disease are lacking. The disease is caused by the mutations in human gene IT15, whose metabolized product is named huntingtin(Htt). HD is caused by expansion of a polyglutamine(polyQ) tract in the exon1 of Htt. Abnormal Htt protein products exist in cells ranging from low-molecular weight species(monomers, oligomers) to small aggregates(globules, fibers) and to inclusion bodies(IBs), which would be an important and critical causation of this disease. However, the etiology of Huntington’s disease is still not well elucidated, so understanding the pathogenesis of this disease is important for HD therapy.Here using a Drosophila model of HD, we showed that altered expression of genes involved in copper metabolism significantly modulates the HD progression; intervention of dietary copper levels also modifies HD phenotypes. Furthermore, copper reduction in the brain decreases the level of oligomerized and aggregated Htt and then slow down the progression of HD. Strikingly, substitution of two potential copper-binding residues of Htt, Met8 and His82, dramatically reduced the toxicity of mutant Htt exon1*-polyQ and completely dissociated its copper-intensifying toxicity.Taken together, our results indicate HD entails two levels of toxicity: the copperfacilitated protein aggregation as conferred by a direct copper binding in the exon1 and the copper-independent polyQ toxicity. The existence of these two parallel pathways converging into Htt toxicity also suggests that an ideal HD therapy would be a multipronged approach that takes both these actions into consideration.