New Insights into CNS Requirements for the Copper - ATPase , ATP 7 A

New Insights into CNS Requirements for the Copper-ATPase, ATP7A 2 Sharon La Fontaine 3 4 1 Deakin University, Geelong, Australia. School of Life and Environmental Sciences, Centre for 5 Molecular and Medical Research and Centre for Cellular and Molecular Biology, Burwood, VIC. 6 3125, Australia. 7 2 The Florey Institute of Neuroscience and Mental Health, Parkville, VIC. 3052, Australia. 8 9 Correspondence to: 10 11 Dr. Sharon La Fontaine 12 Deakin University, Melbourne Campus 13 School of Life and Environmental Sciences, 14 Centre for Cellular and Molecular Biology, 15 221 Burwood Highway, 16 Burwood, VIC, 3125, Australia 17 Email: [email protected] 18 19 Copper is essential for central nervous system (CNS) development and function 20 Copper is indispensable for development and function of the central nervous system (CNS). This is 21 dramatically illustrated by the severe neuropathological deficits in Menkes disease, an X-linked 22 copper deficiency disorder resulting from mutation of the gene that encodes an essential copper 23 transporting P1B-type ATPase, ATP7A. Since its discovery over two decades ago, the role of 24 ATP7A in copper transport and homeostasis has been inextricably linked to satisfying systemic and 25 CNS requirements for copper. In this issue of American Journal of Physiology Cell Physiology, 26 Hodgkinson et al. (2015) (8) describe an important body of work, which for the first time 27 distinguishes the CNS requirement for ATP7A from the CNS requirement for copper. 28 29 The recognition of copper dysregulation as a key pathological feature in prominent 30 neurodegenerative disorders such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) and 31 prion diseases, has intensified research efforts to elucidate the mechanisms of copper regulation in 32 the CNS. Copper is an essential structural or catalytic cofactor for numerous enzymes involved in 33 vital CNS processes such as respiration, neurotransmitter synthesis, activation of neuropeptides and 34 hormones, protection from oxidative damage, myelination, pigmentation and iron metabolism 35 among others. In addition to functioning as cofactor, copper has specific roles in the CNS in 36 neurodevelopment, synaptogenesis and axon extension (5), modulation of neurotransmitter receptor 37 activity and synaptic transmission (2), and in a range of signaling cascades (7). CNS copper is 38 precisely regulated to ensure appropriate levels and distribution for the maintenance of CNS 39 function, and to avoid damage from the redox activity of excess copper. ATP7A is a key player in 40 CNS and systemic copper regulation, functioning at the brain barriers to regulate the entry into and 41 exit of copper from the brain (10). Within cells, ATP7A at the transGolgi network delivers copper 42 into the secretory pathway for metallation of copper-dependent enzymes, and traffics towards the 43 basolateral surface of polarized epithelial cells to expel excess copper. 44 45 Loss of ATP7A from the CNS does not lead to neurodegeneration 46 The study by Hodgkinson et al. (2015) (8) provides new insight into the roles of ATP7A and copper 47 in the CNS by deleting the mouse Atp7a gene from CNS cells, leaving systemic copper homeostasis, 48 and hence brain copper levels, intact. This new mouse model (Atp7a) in which the Atp7a gene 49 was specifically deleted in neural and glial cell precursors, has revealed potentially new roles for 50 Articles in PresS. Am J Physiol Cell Physiol (October 14, 2015). doi:10.1152/ajpcell.00258.2015