Dexamethasone Inhibits Copper-Induced Alpha-Synuclein Aggregation by a Metallothionein-Dependent Mechanism

No Thumbnail Available
File version
Author(s)
McLeary, Fleur A
Rcom-H'cheo-Gauthier, Alexandre N
Kinder, Jessica
Goulding, Michael
Khoo, Tien K
Mellick, George D
Chung, Roger S
Pountney, Dean L
Primary Supervisor
Other Supervisors
Editor(s)
Date
2018
Size
File type(s)
Location
License
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.

Journal Title
Neurotoxicity Research
Conference Title
Book Title
Edition
Volume
33
Issue
2
Thesis Type
Degree Program
School
Publisher link
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement
Item Access Status
Note
This publication has been entered into Griffith Research Online as an Advanced Online Version.
Access the data
Related item(s)
Subject
Biochemistry and cell biology
Clinical sciences
Clinical sciences not elsewhere classified
Neurosciences
Persistent link to this record
Citation
Collections