PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling
PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling
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DOI：
10.1007/s00018-012-0977-6
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发表时间：
2012-06-01
影响因子：
8
通讯作者：
Huttunen, Henri J.
中科院分区：
文献类型：
--
作者：
Kysenius, Kai;Muggalla, Pranuthi;Huttunen, Henri J.
分泌型蛋白酶枯草素/酮素9型（PCSK9）与低密度脂（LDL）受体家族成员LDLR、极低密度脂蛋白受体（VLDLR）和载脂蛋白受体2 （ApoER2）结合，并促进其在细胞内酸性区室中的降解。在肝脏中，LDLR是血液LDL水平的主要控制者，而大脑中的VLDLR和ApoER2介导Reelin信号，这是神经系统正常发育的关键途径。PCSK9在大脑中的表达水平在围产期发育期间在小脑中最高，但在缺血后的成年大脑中也有所增加。PCSK9的功能及其参与神经元凋亡的机制尚不清楚。我们在这里表明，rnai介导的PCSK9的敲低显著降低了缺钾小脑颗粒神经元（CGN）的死亡，这可以通过降低核磷酸化c-Jun和激活的caspase-3的水平以及浓缩的凋亡核来证明。ApoER2蛋白水平在PCSK9 RNAi细胞中升高。敲低ApoER2而不敲低VLDLR足以逆转PCSK9 RNAi提供的保护作用，这表明PCSK9的促凋亡信号传导是由ApoER2功能改变介导的。与脂蛋白受体相关的信号通路的药理抑制表明PCSK9调节神经元凋亡独立于NMDA受体功能，但与ERK和JNK信号通路一致。PCSK9 RNAi还能减少staurosporine诱导的CGN凋亡和神经生长因子缺失的背根神经节神经元轴突变性。我们得出结论，PCSK9通过调节ApoER2水平和相关的抗凋亡信号通路来增强神经元凋亡。
The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments. In the liver, LDLR is a major controller of blood LDL levels, whereas VLDLR and ApoER2 in the brain mediate Reelin signaling, a critical pathway for proper development of the nervous system. Expression level of PCSK9 in the brain is highest in the cerebellum during perinatal development, but is also increased in the adult brain after ischemia. The mechanism of PCSK9 function and its involvement in neuronal apoptosis is poorly understood. We show here that RNAi-mediated knockdown of PCSK9 significantly reduced the death of potassium-deprived cerebellar granule neurons (CGN), as shown by reduced levels of nuclear phosphorylated c-Jun and activated caspase-3, as well as condensed apoptotic nuclei. ApoER2 protein levels were increased in PCSK9 RNAi cells. Knockdown of ApoER2 but not of VLDLR was sufficient to reverse the protection provided by PCSK9 RNAi, suggesting that proapoptotic signaling of PCSK9 is mediated by altered ApoER2 function. Pharmacological inhibition of signaling pathways associated with lipoprotein receptors suggested that PCSK9 regulates neuronal apoptosis independently of NMDA receptor function but in concert with ERK and JNK signaling pathways. PCSK9 RNAi also reduced staurosporine-induced CGN apoptosis and axonal degeneration in the nerve growth factor-deprived dorsal root ganglion neurons. We conclude that PCSK9 potentiates neuronal apoptosis via modulation of ApoER2 levels and related anti-apoptotic signaling pathways.