ArticleProceedings of the National Academy of Sciences of the United States of America2021
Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
36 citing papers in PubMed, 45 citations in OpenAlex.
- From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Emerging role of copper in the pathophysiology of spinal cord injury.Neural regeneration research · 2026Article
- Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.MedComm · 2026Review
- Decreased metallothionein-3 expression in the human spinal cord is a common feature of amyotrophic lateral sclerosis and multiple sclerosis.Scientific reports · 2026Article
- NAMPT orchestrates fibroblast cuproptosis and immune crosstalk during IPF progression.Frontiers in immunology · 2026Article
- Research progress of OTUD7B: from structural function and disease mechanisms to clinical translation.Frontiers in immunology · 2026Review
- Copper Homeostasis and Cuproptosis in Neurological Disorders.Drug design, development and therapy · 2026Review
- The mCells · 2025Review
- Cuproptosis-driven astrocyte reactivity exacerbates experimental cerebral malaria pathogenesis.Parasites & vectors · 2025Article
- Mitochondrial proteins contribute to the pathogenesis of myasthenia gravis.Scientific reports · 2025Article
- Copper homeostasis and cuproptosis in Alzheimer's disease (Review).International journal of molecular medicine · 2025Review
- The Intricate Relationship of Trk Receptors in Brain Diseases and Disorders.Molecular neurobiology · 2025Review
- Spatial protein profiling reveals active roles for astrocytes in the chronic active lesion core during multiple sclerosis.Acta neuropathologica · 2025Article
- Key copper homeostasis genes and inflammatory mechanisms in ischemic stroke: A bioinformatics and experimental study.Functional & integrative genomics · 2025Article
- Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2025Review
- Mammalian copper homeostasis: physiological roles and molecular mechanisms.Physiological reviews · 2025Review
- Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.International journal of molecular sciences · 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
- The physiological and pathophysiological roles of copper in the nervous system.The European journal of neuroscience · 2024Review
Corrections and comments
- Commented on by
Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.