The Role of Copper Homeostasis in Brain Disease

Abstract

In the human body, copper is an important trace element and is a cofactor for several important enzymes involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis. Copper is also necessary for cellular processes, such as the regulation of intracellular signal transduction, catecholamine balance, myelination of neurons, and efficient synaptic transmission in the central nervous system. Copper is naturally present in some foods and is available as a dietary supplement. Only small amounts of copper are typically stored in the body and a large amount of copper is excreted through bile and urine. Given the critical role of copper in a breadth of cellular processes, local concentrations of copper and the cellular distribution of copper transporter proteins in the brain are important to maintain the steady state of the internal environment. The dysfunction of copper metabolism or regulatory pathways results in an imbalance in copper homeostasis in the brain, which can lead to a myriad of acute and chronic pathological effects on neurological function. It suggests a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the relationship between impaired copper homeostasis and neuropathophysiological progress in brain diseases.

Ceruloplasmin‐deficient mice show changes inPTMprofiles of proteins involved in messengerRNAprocessing and neuronal projections and synaptic processes

“…Iron is known to be an important cofactor in a wide range of enzymatic reactions, including the synthesis of enzymes involved in DNA synthesis, mitochondrial electron transport, detoxification, neurotransmitter levels and catecholamine metabolism (Larkin & Rao, 1990, Thirupathi & Chang, 2019). Copper is involved in antioxidant protection, amino acid metabolism, electron transport, hormone production and DNA synthesis and mutations in transporters and chaperones involved in copper metabolism lead to specific neurological diseases distinct from aceruloplasminaemia (An et al, 2022; Sato & Gitlin, 1991). It is therefore possible that the proteomic changes observed in the Cp‐deficient mice may be due to the reduced availability of iron/copper or the lack of Cp's ferroxidase activity as well as effects of Cp deficiency on copper metabolism.…”

Distribution of Copper, Iron, and Zinc in the Retina, Hippocampus, and Cortex of the Transgenic APP/PS1 Mouse Model of Alzheimer’s Disease

“…Copper is a necessary element for maintaining healthy cellular processes in the brain and the eye. In the brain, copper is vital for metalloenzyme functions which are essential in metabolic processes such as energy metabolism, antioxidant-defence mechanisms, and neurotransmitter synthesis [ 46 , 47 ]. In the retina, and similarly in the brain, “free” Cu participates in neurotransmission [ 48 ].…”

Transition metal ions and neurotransmitters: coordination chemistry and implications for neurodegeneration

“…Copper uptake protein 1 (CTR1) is a representative transporter that involves almost 70% of total copper import into the brain. 72 X-ray absorption spectroscopic studies revealed that the human CTR1 trimer binds two Cu( i ) through three-coordinate Cu–S bonds within the Met-Xxx-Xxx-Xxx-Met motif, providing a copper channel. 75,76 Intracellular copper is then appropriately delivered to target enzymes, such as cytochrome c oxidase (C c O) and SOD, by metallochaperones, including COX17 (for C c O) and CCS (for SOD), or stored in glutathione (GSH).…”

“…72,77 Excess copper is removed from brain cells into the cerebrospinal fluid (CSF) followed by being stored in ATP7B for potential transport to the CSF or transported into the blood by ATP7A. 72,78…”