Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities

Tokuda, Eiichi; Okawa, Eriko; Watanabe, S.; Ono, Shin; Marklund, Stefan L.

doi:10.1016/j.nbd.2013.01.001

Cited by 58 publications

(88 citation statements)

References 70 publications

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“…lowering strategies in mutant SOD1 mice, including pharmacological chelation [6,11] or the restriction of copper intake [12], support a deleterious role of copper dyshomeostasis in ALS.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 97%

“…The pathological features of SOD1 G93A mice were evaluated as described previously [6]. All measurements were performed by an observer who was blind to the genotype and treatment.…”

Section: Histopathologymentioning

confidence: 99%

“…Human SOD1 protein level was determined as described previously [6]. Briefly, lumbar spinal cords were homogenized in 20 volumes (w/v) of ice-cold lysis buffer containing 1 % (v/v) Nonidet P-40 and cOmplete, EDTA-free (Roche Applied Science, Indianapolis, IN, USA) protease inhibitor in PBS (pH 7.0).…”

Section: Measurement Of Human Sod1 Protein Levelmentioning

confidence: 99%

“…The expression of the copper uptake proteins, STEAP2 and CTR1, is increased, whereas that of the copper efflux protein, ATP7A, is decreased in the spinal cord of mutant SOD1 mice, regardless of their copper-binding ability [6]. This impairment of the copper trafficking system results in the accumulation of copper ions in the spinal cord [6][7][8][9][10]. The therapeutic effects of copperEiichi Tokuda and Shunsuke Watanabe contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2015

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Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1 G93A ). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1 G93A mice, even if the induction was initiated when peak body weight had decreased by 10 %. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1 G93A aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1 G93A mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.

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“…lowering strategies in mutant SOD1 mice, including pharmacological chelation [6,11] or the restriction of copper intake [12], support a deleterious role of copper dyshomeostasis in ALS.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 97%

“…The pathological features of SOD1 G93A mice were evaluated as described previously [6]. All measurements were performed by an observer who was blind to the genotype and treatment.…”

Section: Histopathologymentioning

confidence: 99%

Section: Measurement Of Human Sod1 Protein Levelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2015

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“…Failure of mutant SOD1 to deliver copper to the mitochondria can impair neuronal energy production and increase oxidative stress (3,13). Demetalation of mutant SOD1 can also result in increased copper concentrations in the spinal cord (14).…”

Section: Mechanismsmentioning

confidence: 99%

ALSUntangled 43: copper

Kolb¹,

Rothstein²,

Valor³

et al. 2017

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Early life metal dysregulation in amyotrophic lateral sclerosis

Figueroa‐Romero

Mikhail

Gennings

et al. 2020

Ann Clin Transl Neurol

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ObjectiveDeficiencies and excess of essential elements and toxic metals are implicated in amyotrophic lateral sclerosis (ALS), but the age when metal dysregulation appears remains unknown. This study aims to determine whether metal uptake is dysregulated during childhood in individuals eventually diagnosed with ALS.MethodsLaser ablation‐inductively coupled plasma‐mass spectrometry was used to obtain time series data of metal uptake using biomarkers in teeth from autopsies or dental extractions of ALS (n = 36) and control (n = 31) participants. Covariate data included sex, smoking, occupational exposures, and ALS family history. Case–control differences were identified in temporal profiles of metal uptake for individual metals using distributed lag models. Weighted quantile sum (WQS) regression was used for metals mixture analyses. Similar analyses were performed on an ALS mouse model to further verify the relevance of dysregulation of metals in ALS.ResultsMetal levels were higher in cases than in controls: 1.49 times for chromium (1.11–1.82; at 15 years), 1.82 times for manganese (1.34–2.46; at birth), 1.65 times for nickel (1.22–2.01; at 8 years), 2.46 times for tin (1.65–3.30; at 2 years), and 2.46 times for zinc (1.49–3.67; at 6 years). Co‐exposure to 11 elements indicated that childhood metal dysregulation was associated with ALS. The mixture contribution of metals to disease outcome was likewise apparent in tooth biomarkers of an ALS mouse model, and differences in metal distribution were evident in ALS mouse brains compared to brains from littermate controls.InterpretationOverall, our study reveals direct evidence that altered metal uptake during specific early life time windows is associated with adult‐onset ALS.

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Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities

Cited by 58 publications

References 70 publications

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

ALSUntangled 43: copper

Early life metal dysregulation in amyotrophic lateral sclerosis

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