The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons.
The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons.
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Fas/Fas 配体死亡受体途径有助于苯丙氨酸诱导皮质神经元细胞凋亡
DOI：
10.1371/journal.pone.0071553
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Huang X;Lu Z;Lv Z;Yu T;Yang P;Shen Y;Ding Y;Fu D;Zhang X;Fu Q;Yu Y
苯丙酮尿症（PKU）是一种由苯丙氨酸羟化酶（PAH）基因突变引起的常染色体隐性氨基酸代谢疾病，通过将神经元暴露于细胞毒性水平的苯丙氨酸（Phe）而导致儿童智力迟钝。最近的一项研究表明，在培养的皮层神经元中，Phe诱导的细胞凋亡中涉及到了Difa介导的（内在的）细胞凋亡途径，但尚不清楚死亡受体（外在的）细胞凋亡途径和内质网（ER）应激相关的细胞凋亡是否也有助于PKU中的神经变性。为了回答这个问题，我们使用特定的抑制剂来阻断神经毒性水平的苯丙氨酸下皮层神经元中的每一个凋亡途径。胱天蛋白酶-8抑制剂Z-IETD-FMK强烈衰减在苯丙氨酸处理的神经元（0.9毫米，18小时）的细胞凋亡，表明参与Fas受体（FasR）介导的细胞死亡受体途径苯丙氨酸毒性。此外，Phe显着增加细胞表面Fas表达和Fas/FasL复合物的形成。使用抗Fas抗体阻断Fas/FasL信号转导可显著抑制Phe引起的细胞凋亡。与此相反，阻断ER应激诱导的细胞死亡途径与salubrinal在苯丙氨酸处理的皮质神经元的凋亡没有影响。这些实验表明，Fas死亡受体途径有助于苯丙氨酸诱导的细胞凋亡，并表明，抑制死亡受体途径可能是一个新的目标在PKU患者的神经保护。
Phenylketonuria (PKU), an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe). A recent study showed that the mitochondria-mediated (intrinsic) apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic) apoptotic pathway and endoplasmic reticulum (ER) stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h), suggesting involvement of the Fas receptor (FasR)-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients.
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影响因子：
3.6
作者：
Huttenlocher, PR
通讯作者：
Huttenlocher, PR
影响因子：
4.3
作者：
Rathinam ML;Watts LT;Narasimhan M;Riar AK;Mahimainathan L;Henderson GI
通讯作者：
Henderson GI
影响因子：
4.4
作者：
Zhang, Yongjun;Zhao, Jing;Jiao, Xianting
通讯作者：
Jiao, Xianting
影响因子：
64.8
作者：
Nakagawa, T;Zhu, H;Yuan, JY
通讯作者：
Yuan, JY
影响因子：
4.8
作者：
Finucane, DM;Bossy-Wetzel, E;Green, DR
通讯作者：
Green, DR