RRC ID 28081
著者 Xiao G, Fan Q, Wang X, Zhou B.
タイトル Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding.
ジャーナル 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.
巻・号 110(37)
ページ 14995-5000
公開日 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
引用数 58
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ショウジョウバエ 7459R-2