Role of Metallothioneins in Neuroprotection against Parkinson's Disease

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Author(s)
McLeary, Fleur Alice
Kinder, J.
Chung, R.
Pountney, Dean Louis
Year published
2014
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Introduction: Parkinson’s disease (PD) has hallmark symptoms of tremor and difficulty initiating movement. It is considered a disease of aging, primarily affecting individuals 65 years and above. Intracellular aggregates of the protein, alpha-synuclein, are the major pathological hallmark of PD and are linked to neurotoxicity. Raised extracellular copper has also been reported in PD and may be linked to alpha-synuclein aggregation. In this project, the potential neuroprotective role of the metal- binding proteins, metallothioneins (MT), has been explored in relation to copper-induced alpha- synuclein aggregation. The specific ...
View more >Introduction: Parkinson’s disease (PD) has hallmark symptoms of tremor and difficulty initiating movement. It is considered a disease of aging, primarily affecting individuals 65 years and above. Intracellular aggregates of the protein, alpha-synuclein, are the major pathological hallmark of PD and are linked to neurotoxicity. Raised extracellular copper has also been reported in PD and may be linked to alpha-synuclein aggregation. In this project, the potential neuroprotective role of the metal- binding proteins, metallothioneins (MT), has been explored in relation to copper-induced alpha- synuclein aggregation. The specific aims of the study were: 1) to investigate if metallothionein transfection can inhibit copper-induced alpha-synuclein aggregation in the SHSY-5Y neuroblastoma cell line; 2) to determine if up-regulation of endogenous expression of metallothionein by use of the synthetic glucocorticoid, dexamethasone, can prevent copper-induced aggregation of alpha-synuclein in SHSY-5Y cells. Methods: SHSY-5Y neuroblastoma cells were treated with 100µM copper to cause alpha-synuclein aggregation. Cells were either transiently transfected with MT-2-GFP or MT-3-GFP isoform expression vectors or treated with dexamethasone at various concentrations to induce endogenous MT expression. Immunofluorescence confocal microscopy was used to quantify alpha- synuclein aggregates under the different treatment conditions. Results: Transfection with MT-2-GFP or MT-3-GFP caused reduced copper-dependent alpha-synuclein aggregation. Dexamethasone treatment resulted in a significant (p, 0.01), dose-dependent up-regulation of MT expression in the SH-SY5Y cell line and a significant reduction in alpha-synuclein intracellular aggregates (p, 0.01). Conclusion: Metallothioneins (MT) show neuroprotective capability against copper-induced alpha- synuclein aggregation. Efficient MT up-regulation by the glucocorticoid, dexamethasone, was found, with a concomitant reduction in alpha-synuclein aggregation.
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View more >Introduction: Parkinson’s disease (PD) has hallmark symptoms of tremor and difficulty initiating movement. It is considered a disease of aging, primarily affecting individuals 65 years and above. Intracellular aggregates of the protein, alpha-synuclein, are the major pathological hallmark of PD and are linked to neurotoxicity. Raised extracellular copper has also been reported in PD and may be linked to alpha-synuclein aggregation. In this project, the potential neuroprotective role of the metal- binding proteins, metallothioneins (MT), has been explored in relation to copper-induced alpha- synuclein aggregation. The specific aims of the study were: 1) to investigate if metallothionein transfection can inhibit copper-induced alpha-synuclein aggregation in the SHSY-5Y neuroblastoma cell line; 2) to determine if up-regulation of endogenous expression of metallothionein by use of the synthetic glucocorticoid, dexamethasone, can prevent copper-induced aggregation of alpha-synuclein in SHSY-5Y cells. Methods: SHSY-5Y neuroblastoma cells were treated with 100µM copper to cause alpha-synuclein aggregation. Cells were either transiently transfected with MT-2-GFP or MT-3-GFP isoform expression vectors or treated with dexamethasone at various concentrations to induce endogenous MT expression. Immunofluorescence confocal microscopy was used to quantify alpha- synuclein aggregates under the different treatment conditions. Results: Transfection with MT-2-GFP or MT-3-GFP caused reduced copper-dependent alpha-synuclein aggregation. Dexamethasone treatment resulted in a significant (p, 0.01), dose-dependent up-regulation of MT expression in the SH-SY5Y cell line and a significant reduction in alpha-synuclein intracellular aggregates (p, 0.01). Conclusion: Metallothioneins (MT) show neuroprotective capability against copper-induced alpha- synuclein aggregation. Efficient MT up-regulation by the glucocorticoid, dexamethasone, was found, with a concomitant reduction in alpha-synuclein aggregation.
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Conference Title
34th Annual Meeting of the Australasian Neuroscience Society
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Copyright Statement
© The Author(s) 2014. The attached file is reproduced here in accordance with the copyright policy of the publisher. For information about this conference please refer to the conference’s website or contact the authors.
Subject
Neurology and Neuromuscular Diseases