The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum.
Copper is essential for brain metabolism, serving as a cofactor to superoxide dismutase, dopamine-beta-hydroxylase, amyloid precursor protein, ceruloplasmin, and other proteins required for normal brain function. The copper-transporting ATPases ATP7A and ATP7B play a central role in distribution of copper in the central nervous system; genetic mutations in ATP7A and ATP7B lead to severe neurodegenerative disorders, Menkes disease and Wilson disease, respectively. Although both ATP7A and ATP7B are required, their specific roles and regulation in the brain remain poorly understood. Using high-resolution imaging and functional assays, we demonstrate that ATP7A and ATP7B show cell-specific distribution in adult cerebellum, have distinct enzymatic characteristics, and are regulated differently during development. ATP7B is continuously expressed in Purkinje neurons (PN) where it delivers copper to the ferroxidase ceruloplasmin. ATP7A is a faster copper transporter than Wilson disease protein as evidenced by faster rates of catalytic reactions. The expression of ATP7A switches during development from PN to Bergmann glia, the cells supporting PN function in adult brain. Inactivation of ATP7B (Wilson disease protein) by gene knock-out induces a striking shift in the expression of the ATP7B target protein, ceruloplasmin, from PN to Bergmann glia, where ATP7A (Menkes disease protein) is present. The induced cell-specific change in expression restores copper delivery to ceruloplasmin via ATP7A. Overall, the results provide evidence for distinct functions of ATP7A and ATP7B in the cerebellum and illustrate a tight link between copper homeostasis in PN and Bergmann glia.
Barnes
Natalie
N
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
Tsivkovskii
Ruslan
R
Tsivkovskaia
Natalia
N
Lutsenko
Svetlana
S
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002531:Cerebellum / Q000254:growth & development*; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D017931:DNA Primers; D018507:Gene Expression Regulation, Developmental; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D011689:Purkinje Cells / Q000502:physiology; D018411:Spodoptera; D014162:Transfection
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D017931:DNA Primers; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases