The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia
The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia
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DOI：
10.1038/jcbfm.2013.139
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发表时间：
2013-11-01
影响因子：
6.3
通讯作者：
Chan, Pak H.
中科院分区：
文献类型：
--
作者：
Yoshioka, Hideyuki;Katsu, Masataka;Chan, Pak H.
早老相关菱形样蛋白（PARL）和高温需要因子A2（HtrA 2）是线粒体完整性的关键调节因子，在细胞凋亡中起关键作用。然而，它们在脑缺血后的作用尚未完全阐明。为了阐明这些作用，对小鼠进行短暂性全脑缺血，并评估纹状体神经元损伤。Western印迹和免疫共沉淀分析显示，PARL和处理HtrA 2定位于线粒体，并且PARL在假手术动物中与HtrA 2结合。缺血后6 ~ 72 h，PARL和HtrA 2在线粒体中的表达明显减少，PARL与HtrA 2的结合消失。与此相反，表达的加工HtrA 2增加缺血后24小时在胞质溶胶中，其中HtrA 2被绑定到X染色体连锁的凋亡相关蛋白（XIAP）。PARL小干扰RNA的管理抑制HtrA 2加工和恶化缺血性神经元损伤。我们的研究结果表明，缺血后PARL的下调是缺血性神经元损伤的关键步骤，它减少了HtrA 2的加工，增加了神经元的脆弱性。此外，在缺血后释放到胞质溶胶中的经处理的HtrA 2通过抑制XIAP而有助于神经元损伤。
The presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2) are key regulators of mitochondrial integrity and play pivotal roles in apoptosis. However, their roles after cerebral ischemia have not been thoroughly elucidated. To clarify these roles, mice were subjected to transient global cerebral ischemia, and striatal neuronal injury was assessed. Western blot and coimmunoprecipitation analyses revealed that PARL and processed HtrA2 localized to mitochondria, and that PARL was bound to HtrA2 in sham animals. Expression of PARL and processed HtrA2 in mitochondria significantly decreased 6 to 72 hours after ischemia, and the binding of PARL to HtrA2 disappeared after ischemia. In contrast, expression of processed HtrA2 increased 24 hours after ischemia in the cytosol, where HtrA2 was bound to X chromosome-linked inhibitor-of-apoptosis protein (XIAP). Administration of PARL small interfering RNA inhibited HtrA2 processing and worsened ischemic neuronal injury. Our results show that downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and that it decreases HtrA2 processing and increases neuronal vulnerability. In addition, processed HtrA2 released into the cytosol after ischemia contributes to neuronal injury via inhibition of XIAP.