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

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

doi:10.1007/s12640-017-9825-7

Cited by 15 publications

(14 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucocorticoids like progesterone are able to induce MT expression 40 . Pre-treatment with the synthetic glucocorticoid analogue dexamethasone (DXM) suppressed the formation of α-synuclein cytoplasmic aggregates in neuroblastoma cells after incubation with copper 27 . In our experiments, 30 µM and 3 µM DXM prolonged MT induction (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…apomorphin, propofol) exert neuron protective effects mainly via up-regulation of MTs 16 , 26 . Treatment of SHSY-5Y cells with dexamethasone reduced Cu-dependent α-synuclein aggregates significantly by MT induction 27 . Miyazaki and colleagues showed that the expression of MT-III and its mRNA was up-regulated in the healthy aged rat brain.…”

Section: Introductionmentioning

confidence: 89%

See 1 more Smart Citation

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans

Pretsch¹,

Rollinger

Schmid

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Neurodegenerative disorders (ND) like Alzheimer’s (AD), Parkinson’s (PD), Huntington’s or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the ‘metal hypothesis of Alzheimer’s disease’ that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO 4 , quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans

Pretsch¹,

Rollinger

Schmid

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Some studies indicate that MT-3, the brain-specific isoform with higher Cu(I) affinity than MT1/2, is decreased in disease [34,35,36,37,38]. Recently, studies have shown that MT induction by the glucocorticoid analogue, dexamethasone, could block Cu-dependent α-syn aggregation [39]. Figure 2A summarizes the regulation of intracellular Cu, interactions between Cu, α-syn, and MT and the induction of MT by dexamethasone.…”

Section: Induction Of Metallothionein As An Anti-copper Therapeuticmentioning

confidence: 99%

Switching on Endogenous Metal Binding Proteins in Parkinson’s Disease

McLeary

Rcom-H'cheo-Gauthier

Goulding

et al. 2019

Cells

Self Cite

View full text Add to dashboard Cite

The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson’s disease (PD) and atypical Parkinson’s diseases is α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger α-syn aggregation, including raised calcium, iron, and copper. Transcriptional inducers have been explored to upregulate expression of endogenous metal-binding proteins as a potential neuroprotective strategy. The vitamin-D analogue, calcipotriol, induced increased expression of the neuronal vitamin D-dependent calcium-binding protein, calbindin-D28k, and this significantly decreased the occurrence of α-syn aggregates in cells with transiently raised intracellular free Ca, thereby increasing viability. More recently, the induction of endogenous expression of the Zn and Cu binding protein, metallothionein, by the glucocorticoid analogue, dexamethasone, gave a specific reduction in Cu-dependent α-syn aggregates. Fe accumulation has long been associated with PD. Intracellularly, Fe is regulated by interactions between the Fe storage protein ferritin and Fe transporters, such as poly(C)-binding protein 1. Analysis of the transcriptional regulation of Fe binding proteins may reveal potential inducers that could modulate Fe homoeostasis in disease. The current review highlights recent studies that suggest that transcriptional inducers may have potential as novel mechanism-based drugs against metal overload in PD.

show abstract

“…Using a model comprising laboratory rats, symptoms of Parkinson disease and damaging of the pars compacta of substantia nigra was initiated by administered copper (106). Copper was also proved an effective catalyzer able to initiate α synuclein aggregation and protective effect of metallothionein was described in the same study (107). The authors inferred that this effect is signifi cant for the development of dementia with Lewy bodies and Parkinson disease and they proved a reduction of the copper effect on α synuclein, when metallothionein is up regulated.…”

Section: Alzheimer Disease and The Other Neurodegenerationsmentioning

confidence: 86%

Copper and copper nanoparticles toxicity and their impact on basic functions in the body

Pohanka¹

2019

BLL

View full text Add to dashboard Cite

Copper is a biogenic metal having multiple functions in basic processes in organisms and it is common in all kingdoms of life. Limited intake of copper is a problem; however, doses of copper exceeding the recommended alimentary source are problematic as well and toxicity is soon manifested. Impact of copper nanoparticles on human health is another serious issue taken into consideration in this review. Regarding to copper toxicity, neurodegenerative disorders including Alzheimer and Parkinson diseases are suspected to be linked to copper toxicity or copper can contribute to their progression. Wilson and Menke diseases are also described as examples of copper intolerance. This paper is focused on the description, literature survey and discussion of the current knowledge about copper and copper nanoparticles toxicity and their involvement in various pathological processes (Tab. 6, Fig. 2, Ref. 171).

show abstract

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

Cited by 15 publications

References 46 publications

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans

Switching on Endogenous Metal Binding Proteins in Parkinson’s Disease

Copper and copper nanoparticles toxicity and their impact on basic functions in the body

Contact Info

Product

Resources

About