Dexamethasone inhibits copper-induced alpha-synuclein aggregation by a metallothionein-dependent mechanism

Fleur A. McLeary, Alexandre N. Rcom-H’cheo-Gauthier, Jessica Kinder, Michael Goulding, Tien K. Khoo, George D. Mellick, Roger S. Chung, Dean L. Pountney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 languageEnglish
Pages (from-to)229–238
Number of pages10
JournalNeurotoxicity Research
Volume33
Issue number2
Early online date24 Oct 2017
DOIs
Publication statusPublished - Feb 2018

Keywords

  • Alpha-synuclein
  • Copper
  • Dementia with Lewy bodies
  • Metallothionein
  • Neurodegeneration
  • Neuroprotection
  • Oxidative stress
  • Parkinson’s disease

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