Copper and the Brain

Field: Neuroscience (Life Sciences)

Copper and the BrainFor over 80 years, copper has been recognized as an essential nutrient in man.It is the third most common trace element in the human body after iron and zinc, with adults having ~ 80 to 100 mg. 1,2Copper is required for cellular respiration, iron oxidation, pigment formation, neurotransmitter biosynthesis, antioxidant defence, peptide amidation and connective tissue formation. 3It is ubiquitous in the brain being most abundant in the basal ganglia, hippocampus, cerebellum, numerous synaptic membranes and in the cell bodies of cortical pyramidal and cerebellar granular neurons; 4 various enzymes depend on copper for their function like tyrosinase, peptidylglycine a-amidating mono-oxygenase, copper/zinc superoxide dismutase, ceruloplasmin, hephaestin, dopamine beta-hydroxylase and cytochrome c oxidase. 5,6The main regulators of cellular copper metabolism are the copper-transporting P-type ATPases: ATP7A and ATP7B and their activity is crucial for development of central nervous system, liver function, connective tissue formation and many other physiologic processes.The classic disease related to ATP7A and ATP7B gene mutation is Wilson's disease and Menkes' disease, while other disorders due to ATP7A gene mutation are occipital horn syndrome and ATP7A-related distal motor neuropathy.The CPC in this issue showcases one of the most fatal presentations of Wilson's disease in the form of fulminant hepatic failure. 7Apart from this disorder of disturbed copper metabolism, copper has been implicated directly or indirectly in the pathogenesis of neurodegenerative disorders like Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.Alzheimer's disease is characterized by progressive cognitive impairment.An increased concentration of copper has been seen in cerebrospinal fluid (CSF) of some patients of Alzheimer's disease. 8Inte raction of copper with amyloid precursor protein and beta-amyloid peptide in the self-aggregating plaques and neurofibrillary tangles may have role in the pathogenesis of this disorder via cellular oxidative stress. 4,5,9,10Elevated levels of copper have also been found in Huntington's disease-a brain disorder that affects a person's ability to think, talk and move.Increased amounts of copper bound to low-affinity-binding sites of huntingtin protein may promote oxidant stress and neurodegeneration. 11he synucleins are a family of redox-active copper-binding proteins. 12a-synuclein has two copper-binding sites and increased formation of a-synuclein aggregates is the direct result of the formation of an a-synuclein-copper complex. 13However, it is seen that the concentration of copper is low in serum and substantia nigra in patients of Parkinson's disease.Whereas the concentration of iron is increased in the Parkinson's disease.Copper-containing enzyme ceruloplasmin has ferroxidase activity and decreased ceruloplasmin level leads to increased iron deposition in the substantia nigra in Parkinson's disease.Iron concentrations of oxidized ceruloplasmin with reduced ferroxidase activity are increased in the CSF, and there is about an 80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of patients with Parkinson's disease. 14he importance of the copper in the development of human nervous system and its implication in the development of neurodegenerative disorders highlight the expanding role of copper in health and disease.Further advances in understanding the functions of copper will pave the way for the therapeutic advances in these disorders.