Abstract
Intracellular aggregates of α-synuclein are the pathological hallmark of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), being linked to neurotoxicity. Multiple triggers of α-synuclein aggregation have been implicated, including raised copper. The potential protective role of the endogenous copper-/zinc-binding proteins, metallothioneins (MT), has been explored in relation to copper-induced α-synuclein aggregation. Up-regulated endogenous expression of MT was induced in SHSY-5Y cells by the synthetic glucocorticoid analogue, dexamethasone. After treatment to induce endogenous MT expression, immunofluorescence confocal microscopy was used to quantify protein aggregates in cells with/without copper treatment. MT induction resulted in significant (p < 0.01), dose-dependent up-regulation of MT expression and significant reduction in Cu-dependent α-synuclein intracellular aggregates (p < 0.01) that could be suppressed by MT-specific siRNA. Ubiquitous (MT-2) and brain-specific (MT-3) isoforms were investigated by transient transfection of the GFP-fusion proteins, observing equivalent α-synuclein aggregate suppression by each. These studies indicate MT induction could have potential in PD/DLB neuroprotective therapy by suppressing α-synuclein aggregation.
Original language | English |
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Pages (from-to) | 229–238 |
Number of pages | 10 |
Journal | Neurotoxicity Research |
Volume | 33 |
Issue number | 2 |
Early online date | 24 Oct 2017 |
DOIs | |
Publication status | Published - Feb 2018 |
Keywords
- Alpha-synuclein
- Copper
- Dementia with Lewy bodies
- Metallothionein
- Neurodegeneration
- Neuroprotection
- Oxidative stress
- Parkinson’s disease