RanBP9 overexpression reduces dendritic arbor and spine density.
RanBP9 overexpression reduces dendritic arbor and spine density.
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DOI：
10.1016/j.neuroscience.2014.01.045
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发表时间：
2014-04-18
期刊：
影响因子：
3.3
通讯作者：
Lakshmana, M. K.
中科院分区：
文献类型：
--
作者：
Wang, H.;Lewsadder, M.;Dorn, E.;Xu, S.;Lakshmana, M. K.
RanBP9是一种多结构域支架蛋白，已知可将细胞外信号与细胞内靶点整合。我们先前证明，在转基因小鼠模型中，RanBP9会增加Aβ的产生和淀粉样斑块负荷，从而导致体内特定的突触前和突触后蛋白丢失。此外，我们发现，从阿尔茨海默病（AD）大脑中分离出的突触小体中，树突棘标志物棘蛋白的水平与RanBP9蛋白水平成反比。在本研究中，我们发现与12月龄的同年龄野生型（WT）对照相比，RanBP9转基因小鼠的皮质第6层锥体神经元以及海马内的树突交叉减少，但在6月龄时没有这种情况。同样，仅在12月龄时，皮质中的树突棘数量减少了30%（p<0.01），但在6月龄时没有减少。在RanBP9转基因小鼠的海马中，12月龄时树突棘密度也降低了（38%，p<0.01）。有趣的是，仅在12月龄时，皮质突触小体中一种在调节树突棘数量方面起关键作用的肌动蛋白结合蛋白——丝切蛋白的磷酸化形式的水平显著降低了26%（p<0.01）。在海马突触小体中，12月龄时丝切蛋白水平降低了36%（p<0.01）。因此，在RanBP9转基因小鼠中，树突分支和树突棘密度与丝切蛋白的磷酸化形式的水平直接相关。同样，在RanBP9转基因小鼠中，皮质突触小体中棘蛋白的水平降低了20%（p<0.01）。这些结果为RanBP9导致突触蛋白丢失提供了物质基础，最重要的是，它也解释了先前在RanBP9转基因小鼠中观察到的空间学习和记忆能力受损的现象。
RanBP9 is a multi-domain scaffolding protein known to integrate extracellular signaling with intracellular targets. We previously demonstrated that RanBP9 enhances Aβ generation and amyloid plaque burden which results in loss of specific pre- and postsynaptic proteins in vivo in a transgenic mouse model. Additionally, we showed that the levels of spinophilin, a marker of dendritic spines were inversely proportional to the RanBP9 protein levels within the synaptosomes isolated from AD brains. In the present study, we found reduced dendritic intersections within the layer 6 pyramidal neurons of the cortex as well as hippocampus of RanBP9 transgenic mice compared to age-matched wild-type (WT) controls at 12-months of age but not at 6 months. Similarly, the dendritic spine numbers were reduced in the cortex at only 12-months of age by 30% (p<0.01), but not at 6 months. In the hippocampus also the spine densities were reduced at 12-months of age (38%, p<0.01) in the RanBP9 transgenic mice. Interestingly, the levels of phosphorylated form of cofilin, an actin binding protein that plays crucial role in the regulation of spine numbers were significantly decreased in the cortical synaptosomes at only 12 months of age by 26% (p<0.01). In the hippocampal synaptosomes, the decrease in cofilin levels were 36% (p<0.01) at 12-months of age. Thus dendritic arbor and spine density were directly correlated to the levels of phosphorylated form of cofilin in the RanBP9 transgenic mice. Similarly, cortical synaptosomes showed a 20% (p<0.01) reduction in the levels of spinophilin in the RanBP9 transgenic mice. These results provided the physical basis for the loss of synaptic proteins by RanBP9 and most importantly it also explains the impaired spatial learning and memory skills previously observed in the RanBP9 transgenic mice.
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