Phospholipase A2 inhibitors or platelet-activating factor antagonists prevent prion replication
Phospholipase A2 inhibitors or platelet-activating factor antagonists prevent prion replication
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DOI：
10.1074/jbc.m404086200
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发表时间：
2004-08-27
影响因子：
4.8
通讯作者：
Williams, A
中科院分区：
文献类型：
--
作者：
Bate, C;Reid, S;Williams, A
朊病毒疾病的一个关键特征是细胞朊病毒蛋白（PrPC）转化为疾病相关的同种型（PrPSc），其沉积被认为会导致神经变性。在这项研究中，药理学的方法被用来确定参与蛋白酶耐药的PrP（PrPres）的形成在三个朊病毒感染的细胞系（ScN2a，SMB和ScGT 1细胞）的代谢途径。每天用磷脂酶A（2）（PLA（2））抑制剂处理这些细胞7天，可防止PrPres的积累。具有抗PLA（2）活性的糖皮质激素也可阻止PrPres的形成，降低SMB细胞的感染性。血小板活化因子（PAF）拮抗剂处理也可降低细胞PrPres含量，而PAF的加入可逆转PLA（2）抑制剂对PrPres形成的抑制作用。用PLA（2）抑制剂或PAF拮抗剂处理7天的ScGT 1细胞在对照培养基中生长12周后，仍没有可检测到的PrPres。用PLA（2）抑制剂或PAF拮抗剂处理未感染的细胞可降低PrPC水平，表明限制细胞PrPC可能会限制感染细胞中朊病毒的形成。这些数据表明PLA（2）和PAF在控制PrPres形成中的关键作用，并将其鉴定为潜在的治疗剂。
A key feature of prion diseases is the conversion of the cellular prion protein (PrPC) into disease-related isoforms (PrPSc), the deposition of which is thought to lead to neurodegeneration. In this study a pharmacological approach was used to determine the metabolic pathways involved in the formation of protease-resistant PrP (PrPres) in three prion-infected cell lines (ScN2a, SMB, and ScGT1 cells). Daily treatment of these cells with phospholipase A(2) (PLA(2)) inhibitors for 7 days prevented the accumulation of PrPres. Glucocorticoids with anti-PLA(2) activity also prevented the formation of PrPres and reduced the infectivity of SMB cells. Treatment with platelet-activating factor (PAF) antagonists also reduced the PrPres content of cells, while the addition of PAF reversed the inhibitory effect of PLA(2) inhibitors on PrPres formation. ScGT1 cells treated with PLA(2) inhibitors or PAF antagonists for 7 days remained clear of detectable PrPres when grown in control medium for a further 12 weeks. Treatment of non-infected cells with PLA(2) inhibitors or PAF antagonists reduced PrPC levels suggesting that limiting cellular PrPC may restrict prion formation in infected cells. These data indicate a pivotal role for PLA(2) and PAF in controlling PrPres formation and identify them as potential therapeutic agents.