Brain-Derived Neurotrophic Factor Inhibits Phenylalanine-Induced Neuronal Apoptosis by Preventing RhoA Pathway Activation
Brain-Derived Neurotrophic Factor Inhibits Phenylalanine-Induced Neuronal Apoptosis by Preventing RhoA Pathway Activation
复制标题
DOI：
10.1007/s11064-009-0084-8
复制
发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Jiao, Xianting
中科院分区：
文献类型：
--
作者：
Zhang, Yongjun;Zhao, Jing;Jiao, Xianting
苯丙酮尿症（PKU）的神经病理学特征是神经元细胞丢失、白色物质异常、树突简化和突触密度降低。神经病理学效应可能是由于高浓度苯丙氨酸的“毒性”，而对阻断这种效应的相关治疗知之甚少。在这项研究中，我们报道了脑源性生长因子（BDNF）保护神经元免受苯丙氨酸诱导的细胞凋亡，并通过K252 a抑制Trk受体或下调TrkB取消BDNF的作用。我们进一步证明，苯丙氨酸诱导的RhoA激活和肌球蛋白轻链磷酸化被BDNF预处理抑制，而苯丙氨酸通过RhoA/Rho相关激酶途径激活了RhoA介导的细胞凋亡。因此，我们的研究表明，BDNF对苯丙氨酸诱导的神经元凋亡的保护作用可能是通过抑制RhoA信号通路通过TrkB受体介导的。总之，这些发现表明BDNF在预防和治疗PKU脑损伤中具有潜在的神经保护作用。
Phenylketonuria (PKU) is neuropathologically characterized by neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction. The neuropathological effect may be due to the 'toxicity' of the high concentration of phenylalanine, while little is known about the related treatments to block this effect. In this study, we reported that brain-derived growth factor (BDNF) protected neurons from phenylalanine-induced apoptosis and inhibition of Trk receptor by K252a or downregulation of TrkB abrogated the effect of BDNF. We further demonstrated that phenylalanine-induced RhoA activation and myosin light chain phosphorylation were inhibited by pretreatment with BDNF, while phenylalanine activates the mitochondria-mediated apoptosis through the RhoA/Rho-associated kinase pathway. Thus our studies indicate that the protective effect of BDNF against phenylalanine-induced neuronal apoptosis is probably mediated by suppression of RhoA signaling pathway via TrkB receptor. Taken together, these findings suggest a potential neuroprotective action of BDNF in prevention and treatment of PKU brain injury.