Neuron-glia: understanding cellular copper homeostasis, its cross-talk and their contribution towards neurodegenerative diseases

Bhattacharjee, Ashima; Ghosh, Sandeepan; Chatterji, Ajanta; Chakraborty, Kaustav

doi:10.1039/d0mt00168f

Cited by 5 publications

(5 citation statements)

References 132 publications

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“…Thermochemistry and/or kinetics are estimated for the different reaction path. Copper is used here as redox metal because of his known role in neurodegeneration [ 108 , 109 , 110 , 111 , 112 , 113 ]. The best protectors, against metal-induced oxidation, are identified based on these data.…”

Section: Resultsmentioning

confidence: 99%

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants

Guzmán‐López

Reina²,

Pérez-González³

et al. 2022

IJMS

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A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson’s and Alzheimer’s diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the ●OH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor–ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.

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Section: Resultsmentioning

confidence: 99%

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants

Guzmán‐López

Reina²,

Pérez-González³

et al. 2022

IJMS

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“…Mammalian astrocytes are known to export Cu that is acquired by neurons for metabolic use (57), and though we cannot assess such a transfer as of yet, it seems reasonable to consider this a strong possibility, particularly given the systemic phenotypes induced by head localized glial cells which may also derive from a transfer of Cu(I). Such a transfer may involve vesicle stores that fuse to release free Cu(I) or Cu(I) binding proteins analogous to mammalian ceruloplasmin (58,59) which supports export of inter-organ transfer of Cu(I) released by the liver. Interestingly, the glia surrounding degenerating neurons in swip-10 mutants appear morphologically normal (15), suggesting that these glia make less use of the relevant Cu(I) dependent processes whose diminished function impact the viability of ensheathed neurons.…”

Section: Discussionmentioning

confidence: 99%

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Rodriguez,

Kalia,

Gibson

et al. 2023

Preprint

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Cuprous copper (Cu(I)) is an essential cofactor for enzymes supporting many cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly dependent on these pathways, with multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, associated with their dysfunction. Key features of Cu(I) contributions to neuronal healthin vivoremain to be defined, owing largely to the complex processes involved in Cu(I) production, intracellular transport, and systemic redistribution. Here, we provide genetic and pharmacological evidence thatswip-10is a critical determinant of systemic Cu(I) levels inC. elegans, with deletion leading to systemic deficits in mitochondrial respiration, production of oxidative stress, and neurodegeneration. These phenotypes can be reproduced in wild-type worms by Cu(I)-specific chelation and offset inswip-10mutants by growth on the Cu(I) enhancing molecule elesclomol, as well as by glial expression of wildtypeswip-10.MBLAC1, the most closely related mammalian ortholog toswip-10, encodes for a pre-mRNA processing enzyme for H3 histone, a protein whose actions surprisingly include an enzymatic capacity to produce Cu(I) via the reduction of Cu(II). Moreover, genome-wide association studies and post-mortem molecular studies implicate reductions ofMBLAC1expression in risk for AD with cardiovascular disease comorbidity. Consistent with these studies, we demonstrate that the deposition of β-amyloid plaques, an AD pathological hallmark, in worms engineered to express human Aβ1-42,is greatly exaggerated by mutation ofswip-10. Together, these studies identify a novel glial-expressed, and pathway for Cu(I) production that may be targeted for the treatment of AD and other neurodegenerative diseases.Significance StatementDevastating neurodegenerative diseases such as Alzheimer’s disease, and Parkinson’s disease are associated with disruptions in copper (Cu) homeostasis. Alterations in Cu(I) give rise to increased oxidative stress burden, mitochondrial and metabolic dysfunction, and can accelerate production and/or potentiate toxicity of disease-associated protein aggregates. Here, using the model systemCaenorhabditis elegans, we establish a role for the geneswip-10in systemic Cu(I) homeostasis. Perturbation of this pathway in worms recapitulates biochemical, histological, and pathological features seen in human neurodegenerative disease. We reveal that these changes can be suppressed pharmacologically and arise whenswip-10expression is eliminated from glial cells. Our work implicatesswip-10and orthologs as key players in Cu(I) homeostasis that may be exploitable to treat multiple neurodegenerative diseases.

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“…Astrocytes play a key role in neuronal circuits that control emotion, learning, and memory, [ 63 ] and their essential functions include regulation of copper homeostasis, metabolic supply of neurons, maintenance of the BBB, and regulation of synaptic transmission and synaptic plasticity. [ 64 ] Astrocytes release various soluble factors, such as glial cell line-derived neurotrophic factor, transforming growth factor-β, basic fibroblast growth factor, and angiopoietin-1, which regulate angiogenic processes and the formation of endothelial cell junctions, thereby maintaining the structural and functional integrity of the BBB. Astrocytes can also use mechano-gated Piezo1 channel-mediated mechanotransduction mechanisms to robustly regulate adult neurogenesis and cognitive function.…”

Section: Mechanisms By Which Copper Overload Affects Cognitive Functionmentioning

confidence: 99%

Copper neurotoxicity: Induction of cognitive dysfunction: A review

Feng,

Zhao,

et al. 2023

Medicine

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Cognitive dysfunction occurs mainly in certain diseases and in the pathological process of aging. In addition to this, it is also widespread in patients undergoing anesthesia, surgery, and cancer chemotherapy. Neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired synaptic plasticity, and lack of neurotrophic support are involved in copper-induced cognitive dysfunction. In addition, recent studies have found that copper mediates cuproptosis and adversely affects cognitive function. Cuproptosis is a copper-dependent, lipoylated mitochondrial protein-driven, non-apoptotic mode of regulated cell death, which provides us with new avenues for identifying and treating related diseases. However, the exact mechanism by which cuproptosis induces cognitive decline is still unclear, and this has attracted the interest of many researchers. In this paper, we analyzed the pathological mechanisms and therapeutic targets of copper-associated cognitive decline, mainly in the context of neurodegenerative diseases, psychiatric and psychological disorders, and diabetes mellitus.

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Neuron-glia: understanding cellular copper homeostasis, its cross-talk and their contribution towards neurodegenerative diseases

Abstract: Over the years, the mechanism of copper homeostasis in various organ systems has gained importance. This is owing to the involvement of copper in a wide range of genetic disorders,...

Cited by 5 publications

References 132 publications

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants

CADMA-Chem: A Computational Protocol Based on Chemical Properties Aimed to Design Multifunctional Antioxidants

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Copper neurotoxicity: Induction of cognitive dysfunction: A review

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