The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum
The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum
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DOI：
10.1074/jbc.m413840200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Lutsenko, S
中科院分区：
文献类型：
--
作者：
Barnes, N;Tsivkovskii, R;Lutsenko, S
铜是大脑代谢所必需的，作为超氧化物歧化酶、多巴胺-β羟化酶、淀粉样前体蛋白、血浆铜蓝蛋白和正常大脑功能所需的其他蛋白质的辅助因子。铜转运ATP酶ATP 7A和ATP 7 B在铜在中枢神经系统中的分布中起核心作用; ATP 7A和ATP 7 B中的基因突变分别导致严重的神经退行性疾病，Menkes病和Wilson病。虽然ATP 7A和ATP 7 B都是必需的，但它们在大脑中的特定作用和调节仍然知之甚少。使用高分辨率成像和功能测定，我们证明了ATP 7A和ATP 7 B在成人小脑中显示细胞特异性分布，具有不同的酶特性，并且在发育过程中受到不同的调节。ATP 7 B在浦肯野神经元（PN）中持续表达，将铜传递给铁氧化酶铜蓝蛋白。ATP 7A是一种比Wilson病蛋白更快的铜转运蛋白，其催化反应速率更快。ATP 7A的表达在发育过程中从PN切换到Bergmann胶质细胞，后者是成年脑中支持PN功能的细胞。通过基因敲除使ATP 7 B（威尔逊病蛋白）失活诱导ATP 7 B靶蛋白铜蓝蛋白的表达从PN到Bergmann神经胶质的显著转变，其中存在ATP 7A（门克斯病蛋白）。诱导的细胞特异性表达变化恢复铜通过ATP 7A递送至血浆铜蓝蛋白。总之，这些结果为ATP 7A和ATP 7 B在小脑中的不同功能提供了证据，并说明了PN和Bergmann胶质细胞中铜稳态之间的紧密联系。
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.