ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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92 citing papers in PubMed, 204 citations in OpenAlex.
- Review
- Copper Complexes: Emerging Micro- and Nanosystems for Dermatological Treatment.Pharmaceutics · 2026Review
- Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.MedComm · 2026Review
- Dynamic PET Imaging of Elesclomol-Facilitated Copper Delivery in Ischemic Stroke Rats.ACS omega · 2026Article
- Decreased metallothionein-3 expression in the human spinal cord is a common feature of amyotrophic lateral sclerosis and multiple sclerosis.Scientific reports · 2026Article
- Copper Homeostasis and Cuproptosis in Neurological Disorders.Drug design, development and therapy · 2026Review
- Imaging Copper Levels during Life in the Brain and beyond Using a Fluorescent Copper Sensor with Multimodal Capacity.Chemical & biomedical imaging · 2025Article
- A primer on copper biology in the brain.Neurobiology of disease · 2025Review
- Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model.Acta neuropathologica communications · 2025Article
- Metal-Induced Genotoxic Events: Possible Distinction Between Sporadic and Familial ALS.Toxics · 2025Review
- Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model.Acta neuropathologica · 2025Article
- Downregulation of Parahippocampal Copper Chaperone for Superoxide Dismutase in Alzheimer's Disease.Brain sciences · 2025Article
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Electrospun nanofiber scaffolds loaded with copper oxide for repairing traumatic brain injury through restoring copper homeostasis and regulating pyroptosis pathway.Burns & trauma · 2025Article
- Copper homeostasis and cuproptosis: implications for neurodegenerative diseases.Frontiers in aging neuroscience · 2025Review
- Cuproptosis and Cu: a new paradigm in cellular death and their role in non-cancerous diseases.Apoptosis : an international journal on programmed cell death · 2024Review
- Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.Metallomics : integrated biometal science · 2024Article
- Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology.Nature communications · 2024Article
- The physiological and pathophysiological roles of copper in the nervous system.The European journal of neuroscience · 2024Review
32 more citing papers are in PubMed but not listed here.
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29 authors at 8 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.
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