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

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, most of them involving neurological symptoms. This highlights the importance of copper and its tight regulation in a complex organ system like the brain. It demands understanding the mechanism of copper acquisition and delivery to various cell types overcoming the limitation imposed by the blood brain barrier. The present review aims to investigate the existing work to understand the mechanism and complexity of cellular copper homeostasis in the two major cell types of the CNS - the neurons and the astrocytes. It investigates the mechanism of copper uptake, incorporation and export by these cell types. Furthermore, it brings forth the common as well as the exclusive aspects of neuronal and glial copper homeostasis including the studies from copper-based sensors. Glia act as a mediator of copper supply between the endothelium and the neurons. They possess all the qualifications of acting as a 'copper-sponge' for supply to the neurons. The neurons, on the other hand, require copper for various essential functions like incorporation as a cofactor for enzymes, synaptogenesis, axonal extension, inhibition of postsynaptic excitotoxicity, etc. Lastly, we also aim to understand the neuronal and glial pathology in various copper homeostasis disorders. The etiology of glial pathology and its contribution towards neuronal pathology and vice versa underlies the complexity of the neuropathology associated with the copper metabolism disorders.