ArticleProceedings of the National Academy of Sciences of the United States of America2013
Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 157 citations in OpenAlex.
- Copper homeostasis and cuproptosis: molecular mechanisms and therapeutic opportunities.Molecular biomedicine · 2026Review
- Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.MedComm · 2026Review
- Brain neuronal CG9593/ANGPTL4 activation mediates paternally acquired motor disorders.Science advances · 2026Article
- Huangqi Baihe Granules alleviate chemotherapy-induced intestinal mucositis in Drosophila and mice.AMB Express · 2026Article
- Copper Homeostasis and Cuproptosis in Neurological Disorders.Drug design, development and therapy · 2026Review
- Review
- AI-Enhanced Transcriptomic Discovery of Druggable Targets and Repurposed Therapies for Huntington's Disease.Brain sciences · 2025Review
- Copper homeostasis and pregnancy complications: a comprehensive review.Journal of assisted reproduction and genetics · 2025Review
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Involvement of copper in cell death and cancer.Apoptosis : an international journal on programmed cell death · 2025Review
- A Julolidine Coupled Azine-based Reversible Chromo-fluorogenic Probe for Specific Detection of CuJournal of fluorescence · 2025Article
- Mammalian copper homeostasis: physiological roles and molecular mechanisms.Physiological reviews · 2025Review
- From copper homeostasis to cuproptosis: a new perspective on CNS immune regulation and neurodegenerative diseases.Frontiers in neurology · 2025Review
- Review
- Inflammation in Metal-Induced Neurological Disorders and Neurodegenerative Diseases.Biological trace element research · 2024Review
- Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Metal Ion Binding to Human Glutaminyl Cyclase: A Structural Perspective.International journal of molecular sciences · 2024Article
- Heavy Metal Interactions with Neuroglia and Gut Microbiota: Implications for Huntington's Disease.Cells · 2024Review
- Copper Metabolism and Cuproptosis: Molecular Mechanisms and Therapeutic Perspectives in Neurodegenerative Diseases.Current medical science · 2024Review
- Copper enhances aggregational toxicity of mutant huntingtin in a Drosophila model of Huntington's Disease.Biochimica et biophysica acta. Molecular basis of disease · 2024Article
12 more citing papers are in PubMed but not listed here.
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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