Reference - Detail
| RRC ID | 28081 |
|---|---|
| Author | Xiao G, Fan Q, Wang X, Zhou B. |
| Title | Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding. |
| Journal | Proc Natl Acad Sci U S A |
| 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. |
| Volume | 110(37) |
| Pages | 14995-5000 |
| Published | 2013-9-10 |
| DOI | 10.1073/pnas.1308535110 |
| PII | 1308535110 |
| PMID | 23980182 |
| PMC | PMC3773747 |
| MeSH | Amino Acid Substitution Animals Animals, Genetically Modified Brain / metabolism Cation Transport Proteins / antagonists & inhibitors Cation Transport Proteins / genetics* Cation Transport Proteins / metabolism* Copper / administration & dosage Copper / metabolism* Copper-Transporting ATPases Disease Models, Animal Drosophila Proteins / antagonists & inhibitors Drosophila Proteins / genetics* Drosophila Proteins / metabolism* Drosophila melanogaster / genetics Drosophila melanogaster / metabolism Female Gene Expression Genes, Insect Humans Huntingtin Protein Huntington Disease / etiology Huntington Disease / genetics* Huntington Disease / metabolism* Nerve Tissue Proteins / genetics* Nerve Tissue Proteins / metabolism* Peptides / genetics Peptides / metabolism* Protein Binding RNA Interference Recombinant Proteins / genetics Recombinant Proteins / metabolism Trinucleotide Repeat Expansion |
| IF | 9.412 |
| Times Cited | 58 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 15 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Drosophila | 7459R-2 |