The Native Copper- and Zinc- Binding Protein Metallothionein Blocks Copper-Mediated Aβ Aggregation and Toxicity in Rat Cortical Neurons
| Autor: | Rannar Sillard, Adele Woodhouse, Claire Howells, Lana Shabala, Adrian K. West, James C. Vickers, Kairit Zovo, Roger S. Chung, William Bennett, Peep Palumaa, Emma D. Eaton, Shannon Ray |
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| Rok vydání: | 2010 |
| Předmět: |
Molecular Sequence Data
lcsh:Medicine chemistry.chemical_element Zinc Metal 03 medical and health sciences 0302 clinical medicine Protein structure mental disorders Extracellular medicine Animals Humans Metallothionein Amino Acid Sequence lcsh:Science Protein Structure Quaternary Cells Cultured 030304 developmental biology Cerebral Cortex Neurons 0303 health sciences Amyloid beta-Peptides Multidisciplinary Chemistry lcsh:R Neurotoxicity Sodium Dodecyl Sulfate medicine.disease In vitro Rats Solubility Biochemistry Biochemistry/Small Molecule Chemistry visual_art Cell Biology/Neuronal and Glial Cell Biology Toxicity visual_art.visual_art_medium lcsh:Q Protein Multimerization Neurological Disorders/Alzheimer Disease Copper 030217 neurology & neurosurgery Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 5, Iss 8, p e12030 (2010) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0012030 |
| Popis: | BACKGROUND: A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (Abeta) plaques. There are compelling data suggesting that Abeta aggregation is catalysed by reaction with the metals zinc and copper. METHODOLOGY/PRINCIPAL FINDINGS: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Abeta1-40 and Abeta1-42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Abeta, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Abeta aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Abeta induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. CONCLUSIONS/SIGNIFICANCE: These results indicate that MTs of the type represented by MT-2A are capable of protecting against Abeta aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Abeta leaving a metal-free Abeta that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Abeta leaves the Abeta in a Zn-bound, relatively inert form. |
| Databáze: | OpenAIRE |
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