Prevention of mutant SOD1 motoneuron degeneration by copper chelatorsin vitro

Azzouz, Mimoun; Poindron, Philippe; Guettier, Severine; Leclerc, Nathalie; Andres, Christian R.; Warter, Jean‐Marie; Borg, Jacques

doi:10.1002/(sici)1097-4695(200001)42:1<49::aid-neu5>3.0.co;2-7

Cited by 43 publications

(19 citation statements)

References 24 publications

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“…Our findings may also have implications for other neurodegenerative disorders such as amyotrophic lateral sclerosis (AL S). Motor neuron loss, in some familial cases of AL S, involves point mutations that promote the interaction of aggregated superoxide dismutasebound Cu with exogenous molecules, resulting in free radical toxicity (Yim et al, 1996;Waggoner et al, 1999;Azzouz et al, 2000). Our work supports this hypothesis by showing that altering the Cu chemistry of a redox active protein can markedly increase its oxidative potential.…”

Section: Discussionsupporting

confidence: 88%

Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

et al. 2002

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The amyloid precursor protein (APP) of Alzheimer's disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid ␤ peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus APP, and APLP2 CuBDs is dependent on conservation of histidine residues at positions corresponding to 147 and 151 of human APP. Intriguingly, APP orthologs with different amino acid residues at these positions had dramatically altered Cu phenotypes. The corresponding C. elegans APL-1 CuBD, which has tyrosine and lysine residues at positions 147 and 151, respectively, strongly protected against Cu-mediated lipid peroxidation and neurotoxicity in vitro. Replacement of histidines 147 and 151 with tyrosine and lysine residues conferred this neuroprotective Cu phenotype to human APP, APLP2, and Xenopus APP CuBD peptides. Moreover, we show that the toxic and protective CuBD phenotypes are associated with differences in Cu binding and reduction. These studies identify a significant evolutionary change in the function of the CuBD in modulating Cu metabolism. Our findings also suggest that targeting of inhibitors to histidine residues at positions 147 and 151 of APP could significantly alter the oxidative potential of APP.

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Section: Discussionsupporting

confidence: 88%

Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

et al. 2002

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“…While Cu 2' could not be used in the present study due to toxicity independent of BDNF or CNTF, copper chelators have been shown to reduce the degeneration of cultured motor neurons that possess the SOD1 mutation (20,21). The combination of copper chelators with BDNF appears to be necessary to obtain full effectiveness of the survival-promoting actions of BDNF in FALS animals (17).…”

Section: Discussionsupporting

confidence: 60%

“…Similar basal levels of apoptosis have been reported by others culturing motor neurons (15). This model is supported by previous studies that have shown that the survival-promoting activities of neurotrophins are inhibited when neurotrophins are co-administered to culture systems with Zn 2' (16,17).…”

Section: Discussionmentioning

confidence: 89%

Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity

Post

Eibl

Ross

2008

Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis is a debilitating disease that results from the deterioration and loss of motor neurons. The neurotoxic potential of Zn(2+), both in vitro and in vivo, has been well established; however, the mechanism(s) of zinc's toxicity remain unclear. Our laboratory has demonstrated that Zn(2+)-mediated inhibition of neurotrophins can induce cell death. The present study investigates the neurotoxic mechanism(s) of this metal ion by assessing zinc's selectivity in altering the neurotrophin BDNF, but not the neural cytokine CNTF, with respect to motor neuron survival. Embryonic day 15 rat spinal motor neuron cultures were maintained in either BDNF or CNTF. Terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining showed that exposure to 100microM Zn(2+) significantly increased the number of pro-apoptotic neurons in cultures maintained with BDNF, while these conditions had no effect on cultures maintained with CNTF. We also demonstrate that BDNF protomer cross-linking efficiency and TrkB receptor cross-linking to BDNF are significantly inhibited by Zn(2+), suggesting that a Zn(2+)-induced change in BDNF conformation inhibits receptor-binding activity. This study reveals a mechanism by which zinc toxicity is mediated via a selective loss in neurotrophin activity resulting in motor neuron death.

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“…1998). Recently, Azzouz et al . (2000) demonstrated a protective role for Cu chelators in a cell culture model of ALS.…”

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confidence: 99%

Homocysteine potentiates copper‐ and amyloid beta peptide‐mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's‐type neurodegenerative pathways

White¹,

Huang²,

Jobling³

et al. 2001

Journal of Neurochemistry

239

125

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Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as re¯ected by the inhibition of toxicity with the Cu (I)-speci®c chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Ab/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote signi®cant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions.

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Prevention of mutant SOD1 motoneuron degeneration by copper chelatorsin vitro

Cited by 43 publications

References 24 publications

Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity

Homocysteine potentiates copper‐ and amyloid beta peptide‐mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's‐type neurodegenerative pathways

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