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![Localization of locus coeruleus in the mouse brain. (Upper panel) Sagittal section, the location of LC is indicated by the grey oval and letters. The vertical dotted line indicates the position of the coronal section. (Lower) Coronal section. The LC is indicated by the grey ovals located on the left and right edge of the ventricle; the upper right insert shows a magnified view of the area that includes one LC and an edge of the ventricle (V); the lower insert shows a higher magnification image of neuronal cell bodies within the LC. The LC is identified by immunostaining for dopamine-β-hydroxylase (DBH, in green) as described in [60]](profile/Clorissa-Washington-Hughes-2/publication/337037031/figure/fig2/AS:900157243662337@1591625619457/Localization-of-locus-coeruleus-in-the-mouse-brain-Upper-panel-Sagittal-section-the.png)
Localization of locus coeruleus in the mouse brain. (Upper panel) Sagittal section, the location of LC is indicated by the grey oval and letters. The vertical dotted line indicates the position of the coronal section. (Lower) Coronal section. The LC is indicated by the grey ovals located on the left and right edge of the ventricle; the upper right insert shows a magnified view of the area that includes one LC and an edge of the ventricle (V); the lower insert shows a higher magnification image of neuronal cell bodies within the LC. The LC is identified by immunostaining for dopamine-β-hydroxylase (DBH, in green) as described in [60]
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Copper (Cu) plays an essential role in the development and function of the brain. In humans, genetic disorders of Cu metabolism may cause either severe Cu deficiency (Menkes disease) or excessive Cu accumulation (Wilson disease) in the brain tissue. In either case, the loss of Cu homeostasis results in catecholamine misbalance, abnormal myelination...
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Context 1
... coeruleus (LC) represents a cluster of approximately 1500 neurons located in the pons (pontine tegmentum) region near the 4th ventricle (Fig. 4, upper panel) [56]. This area of the brain is essential for catecholamine metabolism Fig. 2 Cu distribution pathways in a generalized cell. GSH, glutathione; MT1,2 and MT3; metallothioneins, CCS, copper chaperone for SOD1; Atox1, Cu chaperone for ATP7A and ATP7B.; COXIV cytochrome c reductase. ATP7A delivers Cu to Cu-dependent enzymes within the ...
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... LC. Although LC is small, it sends projections throughout the brain and represents the major source of norepinephrine in the CNS. The LC neurons are responsible for modulation of arousal, attention, and vigilance; they accomplish this function through regulation of target regions in a forebrain [57][58][59]. In the coronal sections of the brain (Fig. 4, lower panel), LC has a characteristic "horn-like" appearance at the edges of the ventricle and can be easily identified by immunostaining for the Cu-dependent enzyme dopamine-β-hydroxylase, DBH, or tyrosine hydroxylase, which is an established marker of noradrenergic neurons (Fig. 4, lower ...
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... a forebrain [57][58][59]. In the coronal sections of the brain (Fig. 4, lower panel), LC has a characteristic "horn-like" appearance at the edges of the ventricle and can be easily identified by immunostaining for the Cu-dependent enzyme dopamine-β-hydroxylase, DBH, or tyrosine hydroxylase, which is an established marker of noradrenergic neurons (Fig. 4, lower ...
Citations
... Elevated Cu levels can increase norepinephrine levels, as observed in individuals with ASD. This association between Cu and neurotransmitter synthesis sheds light on the potential neurobiological mechanisms underlying certain behavioral and cognitive patterns (5,25). ...
This interview delves into the relationship between zinc (Zn) and copper (Cu) in autism spectrum disorder (ASD), featuring insights from Dr. Geir Bjørklund, MD, a Norwegian researcher. Collaborative studies conducted across diverse countries, including China, Slovenia, Romania, Russia, Brazil, and Egypt, consistently reveal altered Zn and Cu levels in individuals with ASD. These findings suggest a potential correlation between elevated Cu levels and increased severity of ASD symptoms. Dr. Bjørklund emphasizes the multifaceted dynamics of metallothioneins (MTs), essential proteins for metal binding and detoxification, and their potential association with Zn deficiency in ASD individuals. The interview illuminates the balance between Zn and Cu within the GABAergic system, implicating these trace elements in synaptic modulation and broader neurobiological functions. Future research directions proposed by Dr. Bjørklund encompass exploring multiple biological mediums for accurate trace element assessment, investigating interactions between different trace elements, and exploring factors influencing trace element levels in various tissues. The significance of Zn supplementation in treating ASD, the implications of MT dysfunction, and the importance of dual monitoring of Cu and Zn during therapy are thoroughly discussed. The conclusion expresses gratitude for Dr. Bjørklund’s invaluable contributions to comprehending the role of Zn and Cu in ASD, highlighting the global relevance of his research and the need for a comprehensive approach to understanding trace element dynamics in this complex neurodevelopmental disorder.
... norepinephrine (regulating several activities, as sleep and emotions) and amide-peptides (over 50% of messenger molecules in the brain), require Cu-dependent enzymes. Dopamine-β-monooxygenase,(EC1.14.17.1) participates in the synthesis of norepinephrine [40], while peptidyl-glycine monooxygenase, EC 1.14.17.3, produces neuropeptides and many hormones (peptides); these need to be amidated at the C-terminal to become biologically active [41]. ...
The brain is a central organ in all animals (with exception of some invertebrates) that controls very relevant roles in the organism. Its activity requires several metabolic pathways in which essential trace elements are important players, and whose performances are related with their (bio)chemical features. Despite their specificities, an integrated approach of the essential trace elements in brain, based on their homoeostasis and competition with other elements (including toxic ones) can promote links among different research fields related with this organ. Roles and hypothetical activities of essential trace elements (chromium, cobalt, copper, iodide, manganese, molybdenum, selenium and zinc) in brain will be discussed.
... By transferring Cu(I) from the small intestine into the blood, ATP7A controls Cu(I) absorption in the human body; hence mutations of the ATP7A gene result in poor physiological dispersion of copper ions to cells 30 , leading to copper aggregation in certain tissues, such as the small intestine and kidneys. The signs and symptoms of Menkes disease and occipital horn disease are caused by diminished activity of copper-containing enzymes 31 . ...
RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in regulation of mammalian genetic diversity. The ability to define and limit access of the enzymatic machinery, to avoid modification of unintended targets, is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation of new candidate genes encoding other elements of the complex could reveal further details of APOBEC mediated mRNA editing. Menkes disease is a recessive X chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper-transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from the macular mouse model of Menkes disease having T > C mutation. Around 35% of the mutated C nucleotide was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field.
... Additionally, it was observed that Pb exposure can upregulate copper transporter 1 (CTR1) and downregulate copper P-type ATPase transporter 7A (ATP7A) in choroidal epithelial cells, resulting in an increase in intracellular copper ion concentrations [29]. Copper is an essential metal element and plays a crucial role in the activities of many enzymes that control a wide range of cellular biochemical and regulatory functions [30]. A recent study has shown that copper exposure in mice can cause oxidative stress, activate the NF-κB pathway, and lead to microglial activation [31]. ...
Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ1-42-treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ1-42, and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ1-42-treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.
... Copper participates in a variety of basic biological processes, including acting as an antioxidant and being an important co-factor for mitochondrial enzymes and respiration. Copper is also used for biosynthesis of neurotransmitters and haem (Lutsenko et al., 2019). Although essential for life, copper is toxic in high concentrations and, as a result, the levels of this metal are under tight homeostatic control. ...
Invasive fungal infections represent a significant global health problem, and present several clinical challenges, including limited treatment options, increasing rates of antifungal drug resistance and compounding comorbidities in affected patients. Metals, such as copper, iron and zinc, are critical for various biological and cellular processes across phyla. In mammals, these metals are important determinants of immune responses, but pathogenic microbes, including fungi, also require access to these metals to fuel their own growth and drive expression of major virulence traits. Therefore, host immune cells have developed strategies to either restrict access to metals to induce starvation of invading pathogens or deploy toxic concentrations within phagosomes to cause metal poisoning. In this Review, we describe the mechanisms regulating fungal scavenging and detoxification of copper, iron and zinc and the importance of these mechanisms for virulence and infection. We also outline how these metals are involved in host immune responses and the consequences of metal deficiencies or overloads on how the host controls invasive fungal infections.
... liver, skin, hair, bone tissues, as well as other internal organs. [1][2][3] The amount of Cu is approximately 100-150 mg in the human body. It participates in the assembly of various enzymes, such as superoxide dismutase 1 (SOD1) and cyclooxygenase (COX). ...
Abstract Copper (Cu) is an essential trace element in the human body that is involved in the formation of several natural enzymes, such as superoxide dismutase and cyclooxygenase. Due to the high density of the outer electron cloud of Cu, which allows the transfer of multiple electrons, Cu is often used as the catalytic center in various metabolic enzymes. However, both deficiency and excessive accumulation of Cu can result in irreversible damage to cells. Therefore, strategies to regulate Cu metabolism, such as Cu exhaustion and Cu supplementation, have emerged as attractive approaches in anticancer therapy, due to the potential damages caused by Cu metabolism disorders. Notably, recent advancements in nanotechnology have enabled the development of nanomaterials that can regulate Cu metabolism, making this therapy applicable in vivo. In this review, we provide a systematic discussion of the physical and chemical properties of Cu and summarize the applications of nanotechnology in Cu metabolism‐based antitumor therapy. Finally, we outline the future directions and challenges of nano‐Cu therapy, emphasizing the scientific problems and technical bottlenecks that need to be addressed for successful clinical translation.
... The isomer L-DOPA is produced in neurons by tyrosine hydroxylase, a Fe-containing enzyme, and is converted to dopamine by the enzyme Ldopa-decarboxylase. The balance of the catecholamine is regulated by the enzyme betahydroxylase, which facilitates the synthesis of norepinephrine from dopamine [40]. Finally, monoamine oxidase (MAO) controls catecholamine hydrolysis. ...
... Cu is a component of dopamine β-hydroxylase and MAO, and Fe of tyrosine hydroxylase, all involved in the catecholamine balance [40] that is altered in disorders of Cu metabolism, e.g., in Wilson disease, the paradigm of non-Cp Cu disbalance [35,41], and in a specific subtype of Alzheimer's disease (AD), the main form of dementia in the elderly, namely, the 'CuAD' [42], typified by non-Cp Cu values higher than normal reference values (>1.6 µmol/L) [35,43]. ...
Dysfunction of the complex cerebral networks underlying wakefulness and awareness is responsible for Disorders of Consciousness (DoC). Traumatic Brain Injury (TBI) is a common cause of DoC, and it is responsible for a multi-dimensional pathological cascade that affects the proper functioning of the brainstem and brain consciousness pathways. Iron (Fe), Zinc (Zn), and Copper (Cu) have a role in the neurophysiology of both the ascending reticular activating system, a multi-neurotransmitter network located in the brainstem that is crucial for consciousness, and several brain regions. We aimed to summarize the role of these essential metals in TBI and its possible link with consciousness alterations. We found that TBI alters many neuronal molecular mechanisms involving essential metals, causing neurodegeneration, neural apoptosis, synaptic dysfunction, oxidative stress, and inflammation. This final pattern resembles that described for Alzheimer’s disease (AD) and other neurological and psychiatric diseases. Furthermore, we found that amantadine, zolpidem, and transcranial direct current stimulation (tDCS)—the most used treatments for DoC recovery—seem to have an effect on essential metals-related pathways and that Zn might be a promising new therapeutic approach. This review summarizes the neurophysiology of essential metals in the brain structures of consciousness and focuses on the mechanisms underlying their imbalance following TBI, suggesting their possible role in DoC. The scenario supports further studies aimed at getting a deeper insight into metals’ role in DoC, in order to evaluate metal-based drugs, such as metal complexes and metal chelating agents, as potential therapeutic options.
... An adequate amount of Copper (Cu) is important for the optimal functioning of the brain as its presence within certain enzymes in the brain helps form key neurotransmitters that allow brain cells communicate to one another (Svetlana et al, 2019). Babies up to the age of 6 months may require 0.20 mg per day (Food and Nutrition, 2001). ...
Background: Breast milk contains various micronutrients which nourishes a baby with nutrition, and therefore the endorsement for exclusive breastfeeding during the first six months after birth. Such micronutrients, if in excess, can have adverse effects on the baby. Objective: The levels of seven micronutrients in breast milk obtained from 27 lactating mothers in the Cape Coast Metropolitan area have been determined using Epithermal Neutron Activation Analysis (ENAA). This technique was used because it is suitable for performing both qualitative and quantitative multi-nutritional analyses on samples, and offers accuracies and sensitivities superior to those attainable by other methods. Materials and Methods: During the analysis, a- 3 mm thick flexible boron was used to cut-off thermal neutrons so as to assess epithermal neutrons, thereby creating an activation energy which measured the levels of micronutrients in the breast milk. The standard reference materials used were the International Atomic Energy Agency (IAEA)-336; IAEA-407, IAEA-350 and National Institute of Standard and Technology (NIST) USA SRM 1577b. The Relative standardization method was used in the quantification of the micronutrients, with an accuracy of about 94.7 %. The micronutrients are Sodium (Na), Magnesium (Mg), Potassium (K), Calcium (Ca), Manganese (Mn), Copper (Cu) and Iodine (I). Results: Except for iodine which had levels below the recommended dietary allowance (RDA), the remaining micronutrients had levels above the upper limit of the RDA, with Manganese being the highest. Conclusion: The levels recorded are directly linked to the food intake of the mothers, and therefore the need for pregnant and lactating mothers to be mindful about what they eat. Children could be exposed to metabolic disorders and diseases as a result of such high levels.
... Dopamine and noradrenalin are catecholamines that play a crucial role in the cortical-subcortical circuitry involved in executive functions. Cu is a component of metallo-proteins and a cofactor of enzymes (dopamine β-hydroxylase, monoamine oxidase) involved in catecholamine balance [41]. Thus, it is reasonable that the Cu imbalance observed in the CuAD subtype could result in an alteration of the catecholamine balance and explain the executive function deficits exhibited by these patients. ...
... Thus, it is reasonable that the Cu imbalance observed in the CuAD subtype could result in an alteration of the catecholamine balance and explain the executive function deficits exhibited by these patients. As a matter of fact, catecholamine balance is altered in other disorders of Cu metabolism, primally in WD [41]. ...
Alzheimer’s disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin Cu (non-Cp Cu) levels were increased in serum/plasma samples. Non-Cp Cu was advocated as a stratification add-on biomarker of a Cu subtype of AD (CuAD subtype). To further circumstantiate this concept, we evaluated non-Cp Cu reliability in classifying subtypes of AD based on the characterization of the cognitive profile. The stratification of the AD patients into normal AD (non-Cp Cu ≤ 1.6 µmol/L) and CuAD (non-Cp Cu > 1.6 µmol/L) showed a significant difference in executive function outcomes, even though patients did not differ in disease duration and severity. Among the Cu-AD patients, a 76-year-old woman showed significantly abnormal levels in the Cu panel and underwent whole exome sequencing. The CuAD patient was detected with possessing the homozygous (c.1486T > C; p.(Ter496Argext*19) stop-loss variant in the RGS7 gene (MIM*602517), which encodes for Regulator of G Protein Signaling 7. Non-Cp Cu as an add-on test in the AD diagnostic pathway can provide relevant information about the underlying pathological processes in subtypes of AD and suggest specific therapeutic options.
... Copper is an essential co-factor for the enzymatic reaction of dopamine β hydroxylase (DBH), which converts dopamine to norepinephrine. In WD, Cu donation to DBH may be impaired, thereby may alter the dopamine-to-norepinephrine ratio [16]. Cerebrospinal fluid dopamine and its metabolites, however, are also affected in neurologic WD due to structural changes in the corpus striatum and midbrain. ...
Movement disorder (MD) is an important manifestation of neurologic Wilson disease (NWD), but there is a paucity of information on dopaminergic pathways. We evaluate dopamine and its receptors in patients with NWD and correlate the changes with MD and MRI changes. Twenty patients with NWD having MD were included. The severity of dystonia was assessed using BFM (Burke-Fahn-Marsden) score. The neurological severity of NWD was categorized as grades I to III based on the sum score of 5 neurological signs and activity of daily living. Dopamine concentration in plasma and CSF was measured using liquid chromatography-mass spectrometry, and D1 and D2 receptor expression at mRNA by reverse transcriptase polymerase chain reaction in patients and 20 matched controls. The median age of the patients was 15 years and 7 (35%) were females. Eighteen (90%) patients had dystonia and 2 (10%) had chorea. The CSF dopamine concentration (0.08 ± 0.02 vs 0.09 ± 0.017 pg/ml; p = 0.42) in the patients and controls was comparable, but D2 receptor expression was reduced in the patients (0.41 ± 0.13 vs 1.39 ± 1.04; p = 0.01). Plasma dopamine level correlated with BFM score (r = 0.592, p < 0.01) and D2 receptor expression with the severity of chorea (r = 0.447, p < 0.05). The neurological severity of WD correlated with plasma dopamine concentration (p = 0.006). Dopamine and its receptors were not related to MRI changes. The central nervous system dopaminergic pathway is not enhanced in NWD, which may be due to structural damage to the corpus striatum and/or substantia nigra.
