Squalestatin cures prion-infected neurons and protects against prion neurotoxicity
Squalestatin cures prion-infected neurons and protects against prion neurotoxicity
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DOI：
10.1074/jbc.m313061200
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发表时间：
2004-04-09
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;Salmona, M;Williams, A
朊病毒疾病的一个关键特征是正常的细胞朊病毒蛋白（PrPC）转化为富含β折叠的疾病相关亚型（PrPSc），其沉积被认为会导致神经变性。在本研究中，角鲨烯合成酶抑制剂角鲨烯抑制素降低了细胞的胆固醇含量，并防止在三个朊病毒感染的细胞系（ScN2a，SMB和ScGT 1细胞）中PrPSc的积累。用角鲨素抑制素处理的ScN2a细胞也被保护免于小胶质细胞介导的杀伤。用角鲨烯抑制素处理神经元导致PrPC远离Triton X-100不溶性脂筏的重新分配。角鲨烯抑制素的这些作用具有剂量依赖性，在纳摩尔浓度下很明显，并被胆固醇部分逆转。此外，未受感染的神经元与角鲨素治疗变得抵抗PrP肽，合成的小朊病毒（sPrP106）或部分纯化的朊病毒制剂的毒性作用。角鲨烯抑制素的保护作用，这是逆转了水溶性胆固醇的加入，与前列腺素E-2的生产，这是与朊病毒病的神经元损伤相关的减少。这些研究表明，胆固醇敏感的过程中控制PrPSc的形成，并在激活与PrP诱导的神经元死亡的信号通路的关键作用。
A key feature of prion diseases is the conversion of the normal, cellular prion protein (PrPC) into beta-sheet-rich disease-related isoforms (PrPSc), the deposition of which is thought to lead to neurodegeneration. In the present study, the squalene synthase inhibitor squalestatin reduced the cholesterol content of cells and prevented the accumulation of PrPSc in three prion-infected cell lines (ScN2a, SMB, and ScGT1 cells). ScN2a cells treated with squalestatin were also protected against microglia-mediated killing. Treatment of neurons with squalestatin resulted in a redistribution of PrPC away from Triton X-100 insoluble lipid rafts. These effects of squalestatin were dose-dependent, were evident at nanomolar concentrations, and were partially reversed by cholesterol. In addition, uninfected neurons treated with squalestatin became resistant to the otherwise toxic effect of PrP peptides, a synthetic miniprion (sPrP106) or partially purified prion preparations. The protective effect of squalestatin, which was reversed by the addition of water-soluble cholesterol, correlated with a reduction in prostaglandin E-2 production that is associated with neuronal injury in prion disease. These studies indicate a pivotal role for cholesterol-sensitive processes in controlling PrPSc formation, and in the activation of signaling pathways associated with PrP-induced neuronal death.