Copper homeostasis and neurodegenerative diseases

Abstract

Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Figure 1

Timeline showing the role of copper in neurodegenerative disease in the literature. Created with Microsoft Office 2016. AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; APP: amyloid precursor protein; ATP7A: Cu-transporting ATPase 1; ATP7B: Cu -transporting ATPase 2; Aβ: amyloid β; CCS: copper chaperone for SOD1; COX: cytochrome c oxidase; COX17: cytochrome c oxidase Cu chaperone 17; CSF: cerebrospinal fluid; CTR1: Cu transporter 1; Cup: cuprizone; HD: Huntington’s disease; MD: Menkes’ disease; MS: multiple sclerosis; MT: metallothionein; PD: Parkinson’s disease; SOD1: superoxide dismutase 1; WD: Wilson’s disease; α-syn: α-synuclein.

Figure 2

Normal copper metabolism. Cu is primarily absorbed in the small intestine and enters hepatocytes through the transporter CTR1. Excess Cu is stored in the liver by MT, while surplus Cu is released into the bloodstream with the mediation of ATP7B. In the blood, Cu binds to ceruloplasmin and is transported to the brain. Cu crosses the BBB via the action of CTR1 and is released into the brain parenchyma by ATP7A. Inside neurons and glial cells, STEAP converts Cu²⁺ to Cu¹⁺, which then enters the cells through the mediation of CTR1 and DMT1. Most Cu¹⁺ is either delivered to ATP7A/B located on the TGN or transferred to the nucleus, facilitated by ATOX1. In the nucleus, the Cu chaperone protein CCS delivers Cu to SOD1, which breaks down superoxide radicals into hydrogen peroxide (H₂O₂). Additionally, Cu participates in mitochondrial respiratory chains and redox pathways by binding to CCO. COX17 binds Cu and transfers it to SCO1 or COX11, enabling Cu to be transferred to CCO. Finally, excessive Cu is expelled through ATP7A/B and can be released into the CSF or transported to the choroid plexus epithelial cells via DMT1 and CTR1. Alternatively, it can be transported back into the bloodstream by ATP7A. Created with Microsoft Office 2016. ATOX1: Antioxidant protein 1; ATP7A: Cu -transporting ATPase 1; ATP7B: ATPase Cu-transporting beta; BBB: blood–brain barrier; BCB: blood–cerebrospinal fluid barrier; CCO: cytochrome oxidase; CCS: Cu chaperone for superoxide dismutase; COX11: cytochrome c oxidase assembly protein COX11; COX17: cytochrome c oxidase Cu chaperone COX17; CP: ceruloplasmin; CSF: cerebrospinal fluid; CTR1: Cu transporter 1; Cu: copper; DMT1: divalent metal transporter 1; H2O2: hydrogen peroxide; MT: metallothionein; SCO1: synthesis of cytochrome c oxidase 1; SOD1: Cu/Zn superoxide dismutase; STEAP: six-segment transmembrane epithelial antigen of prostate; TGN: trans-Golgi network.

Figure 3

Potential mechanisms of neuronal damage attributable to Cu toxicity. (a) Elevated levels of ROS may further compromise mitochondrial integrity, creating a feedback loop that exacerbates ROS generation. Cu significantly enhances mitochondrial ROS production, which subsequently impairs TCA cycle activity. (b) Excessive Cu may also facilitate the polymerization of amyloid oligomers that form following the cleavage of APP. These amyloid plaques increase ROS production and may impair antioxidant function, further exacerbating oxidative stress in the brain. Additionally, Cu phosphorylates tau protein, and its activation leads to the formation of NFTs and subsequent neurodegeneration. (c) Excessive Cu can increase ROS production and promote oxidative stress. Elevated ROS levels induce lipid peroxidation in neuronal cell membranes, resulting in the production of MDA, a cytotoxic compound. ROS also impair the cellular capacity to synthesize antioxidant enzymes, further exacerbating oxidative stress. Additionally, ROS can interact with nucleotides and mitochondria, further activating the caspase-3 cascade in neurons, which can ultimately lead to neuronal death. (d) oxidative stress induced by elevated ROS levels may contribute to neuronal dysfunction and inflammation. Disrupted Cu homeostasis in neuronal cells triggers ROS production, subsequently activating the NF-κB signaling pathway. This activation promotes the transcription of inflammatory genes and the production of pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6. The resultant neurotoxicity exacerbates neurodegeneration. Created with Microsoft Office 2016. APP: Amyloid precursor protein; Cu: copper; GSH: glutathione; IL-1: interleukin-1; IL-6: interleukin- 6; MDA: malondialdehyde; NADPH: nicotinamide adenine dinucleotide phosphate; NFTs: neurofibrillary tangles; NF-κB: nuclear factor-kappa B; P-tau: hyperphosphorylated tau protein; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; TCA: tricarboxylic acid; TNF-α: tumor necrosis factor alpha.

Figure 4

Role of Cu homeostatic imbalance in AD and PD. In the brain tissue of AD patients with AD, there is a decrease in Cu levels, and intracellular Cu deficiency may contribute to excessive phosphorylation of tau, leading to the formation of neurofibrillary tangles. Meanwhile, Cu⁺ can enhance the activity of β-secretase, promoting the production of β-cleaved APP and further facilitating the generation of Aβ. Cu⁺ can also bind with Cu²⁺ to form Aβ oligomers, generating H₂O₂ and promoting OS. Additionally, H₂O₂ reacts with the antioxidant GSH, depleting its antioxidant capacity and causing the denaturation of SOD1. The accumulation of Aβ aggregates ultimately leads to the formation of amyloid plaques, exacerbating neurotoxicity. Imbalances in Cu homeostasis can also contribute to the occurrence and progression of PD. Cu deficiency leads to the aggregation of SOD1 and reduces its activity. Conversely, Cu overload promotes the aggregation of α-synuclein at synapses. Cu can synergistically bind with DA to facilitate the aggregation of misfolded α-synuclein and the generation of ROS, forming fibrils and ultimately resulting in cell death. Created with Microsoft Office 2016. AD: Alzheimer’s disease; APP: amyloid precursor protein; Aβ: amyloid-beta peptides; BACE1: beta-amyloid precursor protein cleaving enzyme 1; Cu: copper; DA: dopamine; GSH: glutathione; H₂O₂: hydrogen peroxide; NFTs: neurofibrillary tangles; OS: oxidative stress; PD: Parkinson’s disease; P-tau: hyperphosphorylated tau protein; ROS: reactive oxygen species; SOD1: superoxide dismutase; α-syn: alpha-synuclein.