Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction.
Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction.
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DOI：
10.1155/2017/4153076
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发表时间：
2017
影响因子：
3.1
通讯作者：
Baucum AJ 2nd
中科院分区：
文献类型：
--
作者：
Hiday AC;Edler MC;Salek AB;Morris CW;Thang M;Rentz TJ;Rose KL;Jones LM;Baucum AJ 2nd
人们对帕金森病 (PD) 中多巴胺神经元丧失后纹状体中发生的信号变化知之甚少。虽然已经观察到激酶活性增加和磷酸酶活性降低，但这些变化的具体后果尚不清楚。磷酸酶，例如蛋白磷酸酶 1 (PP1)，具有高度混杂性，并通过靶向蛋白质获得底物选择性。 Spinophilin 是纹状体树突棘突触后密度中富集的主要 PP1 靶向蛋白。在 PD 动物模型中，亲旋蛋白与 PP1 的关联随着 PP1 活性的降低而增加。使用基于蛋白质组学的方法，我们观察到多巴胺耗竭引起的亲旋蛋白与纹状体中多种蛋白质类别的结合减少。具体来说，在多巴胺耗尽的纹状体中，亲旋蛋白与神经丝介质（NF-M）的关联减少。使用异源细胞系，我们确定 Spinophilin 与 NF-M 的结合需要蛋白激酶 A 催化亚基的过度表达，并被细胞周期蛋白依赖性蛋白激酶 5 所减少。从功能上讲，我们证明 Spinophilin 可以降低 NF-M 磷酸化。我们的数据确定了在 PD 动物模型中观察到的亲脊髓蛋白与 NF-M 相关病理变化的调节机制和假定后果。
Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M) in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD.