Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons
Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons
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苯丙氨酸对培养的皮质神经元中 Rac1、Cdc42 和 RhoA 表达和活性的不同影响
DOI：
10.1203/pdr.0b013e31806772be
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发表时间：
2007-07
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
苯丙酮尿症（PKU）的特点是苯丙氨酸浓度高，可导致智力低下。未经治疗的苯丙酮尿症患者的特征性病理变化之一是脑中轴突、树突和突触的数量减少。这被认为是由于苯丙氨酸和/或其代谢产物的毒性作用，然而，潜在的机制仍不清楚。在这项研究中，我们观察到苯丙氨酸减少培养的神经元树突和树突棘的数量。我们进一步证明，苯丙氨酸下调Rac 1，Cdc 42和RhoA mRNA和蛋白质的表达。下拉实验表明，苯丙氨酸导致Rac 1/Cdc 42活性下降，但增加RhoA活性。显性负性RhoA的表达或Rho相关激酶特异性抑制剂Y-27632的处理部分抑制了苯丙氨酸诱导的树突数量减少。总之，我们已经证明，苯丙氨酸影响Rac 1，Cdc 42和RhoA的表达和活性。此外，RhoA信号参与苯丙氨酸对树突分支的抑制作用。这些结果可能提供了一个重要的洞察苯丙氨酸诱导的树突异常的分子机制，特别是在苯丙酮尿症神经元损伤。
Phenylketonuria (PKU) is characterized by a high concentration of phenylalanine, which can lead to mental retardation. One of the characteristic pathologic changes in untreated phenylketonuria patients is a reduction in the number of axons, dendrites, and synapses in the brain. This is thought to be due to the toxic effects of phenylalanine and/or its metabolites, however, the underlying mechanism remains unclear. In this study, we observed that phenylalanine reduced the number of dendrites and dendritic spines in cultured neurons. We further demonstrated that phenylalanine down-regulated Rac1, Cdc42, and RhoA mRNA and protein expression. Pull-down assays indicated that phenylalanine caused a decrease in Rac1/Cdc42 activity but increased RhoA activity. Expression of a dominant negative RhoA or treatment with a Rho-associated kinase specific inhibitor, Y-27632, partly inhibited the phenylalanine-induced decrease in dendrite numbers. In conclusion, we have demonstrated that phenylalanine affects the expression and activity of Rac1, Cdc42, and RhoA. Furthermore, RhoA signaling is involved in the inhibitory effect of phenylalanine on dendritic branching. These results may provide an important insight into the molecular mechanism underlying phenylalanine-induced abnormalities of dendrites, specifically in phenylketonuria neuronal injury.
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DOI：
10.1523/jneurosci.23-08-03118.2003
发表时间：
2003-04
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
Ethan K. Scott;J. Reuter;L. Luo
通讯作者：
Ethan K. Scott;J. Reuter;L. Luo
DOI：
10.1007/978-94-015-9460-8_17
发表时间：
2000
期刊：
--
影响因子：
--
作者：
Hai Li;Zhenbiao Yang
通讯作者：
Hai Li;Zhenbiao Yang
影响因子：
3.6
作者：
Huttenlocher, PR
通讯作者：
Huttenlocher, PR
DOI：
10.1002/ajmg.1320440412
发表时间：
1992-11-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
KORNGUTH, S;GILBERTBARNESS, E;HEGSTRAND, L
通讯作者：
HEGSTRAND, L
影响因子：
21.3
作者：
Xiao-Bing Yuan;M. Jin;Xiaohua Xu;Yuan-quan Song;Chien-ping Wu;M. Poo;S. Duan
通讯作者：
Xiao-Bing Yuan;M. Jin;Xiaohua Xu;Yuan-quan Song;Chien-ping Wu;M. Poo;S. Duan