Comstra Heather S, McArthy Jacob, Rudin-Rush Samantha, Hartwig Cortnie, Gokhale Avanti, Zlatic Stephanie A, Blackburn Jessica B, Werner Erica, Petris Michael, D'Souza Priya, Panuwet Parinya, Barr Dana Boyd, Lupashin Vladimir, Vrailas-Mortimer Alysia, Faundez Victor
Departments of Cell Biology, Emory University, Atlanta, United States.
School of Biological Sciences, Illinois State University, Normal, United States.
Elife. 2017 Mar 29;6:e24722. doi: 10.7554/eLife.24722.
Genetic and environmental factors, such as metals, interact to determine neurological traits. We reasoned that interactomes of molecules handling metals in neurons should include novel metal homeostasis pathways. We focused on copper and its transporter ATP7A because ATP7A null mutations cause neurodegeneration. We performed ATP7A immunoaffinity chromatography and identified 541 proteins co-isolating with ATP7A. The ATP7A interactome concentrated gene products implicated in neurodegeneration and neurodevelopmental disorders, including subunits of the Golgi-localized conserved oligomeric Golgi (COG) complex. COG null cells possess altered content and subcellular localization of ATP7A and CTR1 (SLC31A1), the transporter required for copper uptake, as well as decreased total cellular copper, and impaired copper-dependent metabolic responses. Changes in the expression of ATP7A and COG subunits in neurons altered synapse development in larvae and copper-induced mortality of adult flies. We conclude that the ATP7A interactome encompasses a novel COG-dependent mechanism to specify neuronal development and survival.
遗传因素和环境因素（如金属）相互作用，共同决定神经特征。我们推断，神经元中处理金属的分子相互作用组应包含新的金属稳态途径。我们聚焦于铜及其转运蛋白ATP7A，因为ATP7A基因的无效突变会导致神经退行性变。我们进行了ATP7A免疫亲和层析，并鉴定出541种与ATP7A共同分离的蛋白质。ATP7A相互作用组富集了与神经退行性变和神经发育障碍相关的基因产物，包括高尔基体定位的保守寡聚高尔基体（COG）复合体的亚基。COG基因缺失的细胞中，ATP7A和CTR1（SLC31A1，铜摄取所需的转运蛋白）的含量及亚细胞定位发生改变，细胞总铜含量降低，铜依赖性代谢反应受损。神经元中ATP7A和COG亚基表达的变化改变了幼虫的突触发育以及成年果蝇的铜诱导死亡率。我们得出结论，ATP7A相互作用组包含一种新的依赖于COG的机制，该机制决定神经元的发育和存活。
