Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: a review

Abstract

The effect of redox metals such as iron and copper on multiple sclerosis and amyotrophic lateral sclerosis has been intensively studied. However, the origin of these disorders remains uncertain. This review article critically describes the physiology of redox metals that produce oxidative stress, which in turn leads to cascades of immunomodulatory alteration of neurons in multiple sclerosis and amyotrophic lateral sclerosis. Iron and copper overload has been well established in motor neurons of these diseases' lesions. On the other hand, the role of other metals like cadmium participating indirectly in the redox cascade of neurobiological mechanism is less studied. In the second part of this review, we focus on this less conspicuous correlation between cadmium as an inactive-redox metal and multiple sclerosis and amyotrophic lateral sclerosis, providing novel treatment modalities and approaches as future prospects.

Fig. 1. ROS and anti-ROS cellular machinery involved intracellular homeostasis of protein/lipid/DNA

. ROS is formed by complex I and III in the electron transport chain in the inner layer of mitochondria through oxidative phosphorylation process, consuming oxidation of NADH or FADH to generate potential energy for protons^,,.

Fig. 2. Iron metabolism in the brain. Astrocytes express CP to oxidize Fe²⁺

. Oligodendrocytes, a primary target in inflammatory attack, and synthesize Tf that controls intracellular iron transport. Microglia represent DMT1, APP, and ferritin, assisting neurons to maintain iron hemostasis in the brain environment. They also protect normal neuron function by iron regulation. The ferric iron (Fe³⁺) derived from diet, excreted enterocytes, and reticulocytes binds to transferrin (Tf). This combination uptake in the endothelial surfaces in the BBB is mediated by TfR. Fe³⁺ releases from Tf-TFR complex in the endosome and is catalyzed to ferrous iron (Fe²⁺). Thereby, TfR is recycled to bind to the iron Tf complex in the plasma. Alternatively, Fe²⁺ is transported to cytosol of endothelial cells and extracellular fluid by DMT1 and FPN1, respectively. In addition, released Fe²⁺ is quickly converted to Fe³⁺ by CP, expressed by both astrocytes and endothelial cells followed by bonding to Tf or low molecular weight molecules (e.g., citrate and ATP). Non-Tf-bound iron (NTBI) synthesized in the cytosol is the iron source for oligodendrocytes and astrocytes where Tf is highly saturated by iron^,

Fig. 3

Neuronal iron homeostasis

Fig. 4. Copper homeostasis in the brain.

A group of transmembrane proteins including Ctr 1, DMT1, ATPases (ATP7A and ATP7B) play crucial roles for intracellular copper regulation. Ctr1 is an essential copper transporter expressed in intestinal and brain cells to handle copper influx. DMT1 is also expressed in brain tissues and may contribute to copper uptake^,. ATP7a acts as a critical source of brain copper and mediates copper movement across the basolateral membrane into the extra-vascular space of the brain. It also exports copper for subsequent incorporation into Cu-dependent enzymes^,,. ATP7b also transfers copper across membranes, however, the function of ATP7b is less clear compared to ATP7a^,. Copper chaperone proteins control copper traffic and delivery into specific cellular targets. Moreover, chaperone for SOD1 (CCS), chaperone for cytochrome C oxygenase (Cox17), anti-oxidant protein 1 (Atox 1) deliver copper to SOD1, cytochrome oxidase, and ATP7a, respectively^,,. MTs are low molecular weight proteins with neuroprotective roles and a high number of cysteine residues for metal binding such as copper and zinc^,,. There are four types of MTs in mammals. MT1 and MT2 are expressed in all tissues, MT3 exists in CNS, and MT4 is found in the stratified squamous epithelia. MTs are known as copper buffers in the glutamatergic synapse where excess copper induces a high level of MTs^,.

Fig. 5. Cadmium influence on intra- and extracellular neuronal homeostasis, contributing to CNS pathophysiology.

Extracellular cadmium has an estrogen-like effect, disturbing hormonal balance via the hypothalamic-pituitary-gonadal pathway. Intracellular cadmium disturbs neurogenesis and leads to neuronal apoptosis and ROS by impairing mitochondria signaling and inhibition of Jak/Stat signaling. The cadmium accumulation in the brain alters gene expression and causes epigenetic effects through DNA binding. Moreover, it leads to oxidative stress via inhibition of antioxidant enzymes, depletion of antioxidants, dislocation of redox active metals, and suppression of the mitochondrial electron transport chain^,. The replacement of iron and copper by cadmium, and thereby the increase of free iron and copper content, generate hydroxyl radicals and promote oxidative stress via Fenton’s reaction^,,,. Additionally, the activity of different antioxidant enzymes, including Cu/Zn SOD1, glutathione peroxidase, glutathione reductase, and catalase is altered by cadmium intoxication. Cadmium-induced selenium deficiency causes depletion of glutathione peroxidase. Also, cellular antioxidant GSH is disrupted by cadmium and results in the elevation of ROS. The excess of intracellular ROS inhibits the neural janus kinase (Jak) and tyrosine kinase, and leads to disruption of neural mitochondria