ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis
ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis
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DOI：
10.1016/j.mcn.2006.11.018
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Ronnett, Gabriele V.
中科院分区：
文献类型：
--
作者：
El Meskini, Rajaa;Crabtree, Kelli L.;Ronnett, Gabriele V.
门克斯病 (MD) 是一种由铜转运蛋白 ATP7A（一种 P 型 ATP 酶）突变引起的神经退行性疾病。我们之前使用嗅觉系统来证明 ATP7A 的表达是发育性的，而不是组成性的、受调节的，在突触发生过程中达到峰值，此时它以不依赖于铜的方式在延伸轴突中高表达。尽管未知与轴突功能相关，但我们探讨了突变体 ATP7A 无法支持轴突生长导致 MD 中神经变性的可能性。对斑点斑纹 (Atp7a(Mobr)) 小鼠（MD 的啮齿动物模型）嗅觉系统的体内分析表明 ATP7A 缺乏会影响嗅觉感觉神经元 (OSN) 的成熟。 OSN 轴突投射和二尖瓣/簇状细胞树突生长中断导致 Atp7a(Mobr) 小鼠嗅球突触完整性改变和肾小球紊乱。我们的数据表明，MD 中观察到的神经元异常是特定年龄依赖性发育缺陷的结果。这项研究证明了 ATP7A 和/或铜在轴突生长和突触发生中的作用，并将进一步帮助确定 MD 特征的神经病理学原因。 (c) 2006 Elsevier Inc. 保留所有权利。
Menkes disease (MD) is a neurodegenerative disorder caused by mutations in the copper transporter, ATP7A, a P-type ATPase. We previously used the olfactory system to demonstrate that ATP7A expression is developmentally, not constitutive, regulated, peaking during synaptogenesis when it is highly expressed in extending axons in a copper-independent manner. Although not known to be associated with axonal functions, we explored the possibility that the inability of mutant ATP7A to support axon outgrowth contributes to the neurodegeneration seen in MD. In vivo analysis of the olfactory system in mottled brindled (Atp7a(Mobr)) mice, a rodent model for MD, demonstrates that ATP7A deficiency affects olfactory sensory neuron (OSN) maturation. Disrupted OSN axonal projections and mitral/tufted cell dendritic growth lead to altered synapse integrity and glomerular disorganization in the olfactory bulbs of Atp7a(Mobr) mice. Our data indicate that the neuronal abnormalities observed in MD are a result of specific age-dependent developmental defects. This study demonstrates a role for ATP7A and/or copper in axon outgrowth and synaptogenesis, and will further help identify the cause of the neuropatbology that characterizes MD. (c) 2006 Elsevier Inc. All rights reserved.