Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding

Abstract

Huntington disease (HD) is a progressive neurodegenerative disorder caused by dominant polyglutamine (polyQ) expansion within the N terminus of huntingtin (Htt) protein. Abnormal metal accumulation in the striatum of HD patients has been reported for many years, but a causative relationship has not yet been established. Furthermore, if metal is indeed involved in HD, the underlying mechanism needs to be explored. Here using a Drosophila model of HD, wherein Htt exon1 with expanded polyQ (Htt exon1-polyQ) is introduced, we show that altered expression of genes involved in copper metabolism significantly modulates the HD progression. Intervention of dietary copper levels also modifies HD phenotypes in the fly. Copper reduction to a large extent decreases the level of oligomerized and aggregated Htt. Strikingly, substitution of two potential copper-binding residues of Htt, Met8 and His82, completely dissociates the copper-intensifying toxicity of Htt exon1-polyQ. Our results therefore indicate HD entails two levels of toxicity: the copper-facilitated 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.

Biological metals and metal-targeting compounds in major neurodegenerative diseases

“…281 Modulation of copper homeostasis by genetic and dietary interventions strikingly modifies disease progression in a HTT exon 1 Drosophila model of HD. 282 Copper interaction with mutant HTT promoted toxicity in this model, which was rescued by substituting key copper-coordinating residues, Met8 and His82. 282 The breakdown in metal homeostasis in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a disease in which motor neurons in the spinal cord and brain progressively deteriorate leading to paralysis and death.…”

Copper signaling in the brain and beyond

“…Interestingly, copper also alters the activity of glycogen synthase kinase 3β (GSK3β), an enzyme involved in regulating APP processing, linking copper to APP biology through multiple mechanisms (48,49). Additionally, pathological aggregation of both APP and Htt may be mediated by copper binding (50,51). Indeed, Zhou and co-workers showed that when potential copper-binding residues on Htt were mutated, changes in neural copper homeostasis no longer influenced Htt aggregation (51), suggesting that copper levels directly impact HD progression.…”

“…Additionally, pathological aggregation of both APP and Htt may be mediated by copper binding (50,51). Indeed, Zhou and co-workers showed that when potential copper-binding residues on Htt were mutated, changes in neural copper homeostasis no longer influenced Htt aggregation (51), suggesting that copper levels directly impact HD progression. Finally, aggregation of mutant forms of SOD1, an enzyme that requires copper and zinc cofactors for catalytic function, leads to ALS (52,53), and the disease course can be modulated by changes in dietary zinc and copper (54).…”

Manganese and Huntington Disease

“…68 Despite this potentially positive role of copper in inducing mutant aggregation, reduction of copper via chelation or via genetic knock-down of copper transporters has mitigated HD pathology in both mouse and fly models of HD while simultaneously reducing aggregation. 69,70 Copper treatment also further decreased the life span of HD flies. 70 These models, however, express only exon1 of the mutant gene, and aggregation may be a necessary step in pathology with these imperfect model systems.…”