Increase of oxidative stress by a novel PINK1 mutation, P209A
Increase of oxidative stress by a novel PINK1 mutation, P209A
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DOI：
10.1016/j.freeradbiomed.2012.12.008
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发表时间：
2013-05-01
影响因子：
7.4
通讯作者：
Fu, Wen-Mei
中科院分区：
文献类型：
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作者：
Chien, Wei-Lin;Lee, Tzeng-Ruei;Fu, Wen-Mei
人类PTEN诱导的蛋白激酶1（PINK 1）基因突变是第二种最常见的隐性帕金森病（PD）的原因。我们从68例早发性PD患者队列中发现了一个PINK 1杂合子突变P209 A。从31岁开始，该患者出现不对称运动迟缓伴僵硬，对左旋多巴有反应。[F-18]-氟多巴PET扫描显示双侧基底神经节多巴摄取减少。PINK 1 P209 A突变体的转染增强了SH-SY 5 Y细胞中H2 O2诱导的细胞死亡、ROS产生和caspase-3活化。血红素氧合酶-1（HO-1）诱导响应H2 O2和MPP+处理受损的PINK 1 P209 A突变体的过表达。此外，TNF α处理后的SOD 2诱导也受到PINK 1 P209 A突变的抑制。Ala和ERK参与氧化应激后HO-1的诱导。与空载体转染的细胞相比，PINK 1 P209 A突变体细胞暴露于H2 O2或MPP+后Ala和ERK的磷酸化也受到抑制。这些结果表明PINK 1激酶结构域中的P209 A缺陷通过一种新的途径抑制氧化应激诱导的HO-1和SOD 2诱导，这可能加速PINK 1缺陷的PD的神经变性。皇冠版权所有（C）2012由Elsevier Inc.发布。All rights reserved.
Mutation in the human PTEN-induced protein kinase 1 (PINK1) gene is responsible for the second most common form of recessive Parkinson disease (PD). We have identified a single heterozygous PINK1 mutation, P209A, from a cohort of 68 patients with early onset PD. From age 31, this patient developed an asymmetric bradykinesia with rigidity that was L-DOPA responsive. An [F-18]-fluorodopa PET scan showed reduced DOPA uptake in the bilateral basal ganglia. The H2O2-induced cell death, ROS production, and caspase-3 activation in SH-SY5Y cells were enhanced by the transfection of the PINK1 P209A mutant. The heme oxygenase-1 (HO-1) induction in response to H2O2 and MPP+ treatment was impaired by the overexpression of the PINK1 P209A mutant. In addition, SOD2 induction after TNF alpha treatment was also inhibited by the PINK1 P209A mutation. Ala and ERK are involved in HO-1 induction after oxidative stress. The phosphorylation of Ala and ERK after exposure to H2O2 or MPP+ was also inhibited in PINK1 P209A mutant cells compared with empty-vector-transfected cells. These results indicate a novel pathway by which the P209A defect in the PINK1 kinase domain inhibits oxidative stress-induced HO-1 and SOD2 induction, which may accelerate the neurodegeneration in PD with PINK1 defect. Crown Copyright (C) 2012 Published by Elsevier Inc. All rights reserved.