The Physiological and Pathophysiological Roles of Copper in the Nervous System.
European journal of neuroscience/EJN European journal of neuroscience(2024)
摘要
Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-beta-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling. Copper is absorbed in the small intestines via the copper transporter CTR1 and the divalent metal transporter DMT1 and is released into the circulation by the copper transporter ATP7A. Copper is then transported to the liver where it is stored and delivered by ATP7B to the copper binding protein ceruloplasmin. In the brain, these copper transporters, as well SOD1, facilitate essential physiological functions including synaptogenesis, synaptic activity, regulation of circadian rhythms and antioxidant activity and the loss or mutation of such proteins results in various diseases. image
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关键词
ATP7A,ATP7B,copper homeostasis,redox,SOD1
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