Prion replication alters the distribution of synaptophysin and caveolin 1 in neuronal lipid rafts
Prion replication alters the distribution of synaptophysin and caveolin 1 in neuronal lipid rafts
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DOI：
10.1016/s0002-9440(10)63439-6
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发表时间：
2004-11-01
影响因子：
6
通讯作者：
Soto, C
中科院分区：
文献类型：
--
作者：
Russelakis-Carneiro, M;Hetz, C;Soto, C
朊病毒疾病发病机制中的主要事件是细胞朊病毒蛋白（PrPC）转化为异常的蛋白酶抗性朊病毒蛋白（PrPres）。PrPC是位于脂筏或抗洗涤剂膜（DRM）中的GPI锚定蛋白。在这里，我们描述了关联的PrP与DRMs在神经元细胞体和轴突的过程中，小鼠瘙痒症和它的关系与分布的PrP相互作用蛋白小窝蛋白I和突触素。在神经元细胞损失的证据之前，瘙痒病感染触发了PrPres在视网膜和视神经的DRM中的积累。大多数PrPres在疾病进展的不同阶段仍然与脂筏相关。与PrPres相反，在瘙痒病感染过程中，视网膜和视神经中的小窝蛋白1和突触素转移到非DRM组分。DRMs中PrPres的积累与其组成的一般变化无关，因为在疾病的晚期之前，未观察到蔗糖梯度中总蛋白分布或鞘糖脂GM 1或Thy-1的浮选特性的变化。然而，在视神经和视网膜中观察到总胆固醇水平增加。仅在疾病的晚期观察到神经元细胞体的数量减少，这表明突触异常是最终导致神经元死亡的神经元功能障碍的最早迹象。这些结果表明，朊病毒复制触发异常定位的小窝蛋白1和突触素，这反过来可能会改变神经元的功能。
The main event in the pathogenesis of prion diseases is the conversion of the cellular prion protein (PrPC) into the abnormal, protease-resistant prion protein (PrPres). PrPC is a GPI-anchored protein located in lipid rafts or detergent-resistant membranes (DRMs). Here we describe the association of PrP with DRMs in neuronal cell bodies and axons during the course of murine scrapie and its relation with the distribution of the PrP-interacting proteins caveolin I and synaptophysin. Scrapie infection triggered the accumulation of PrPres in DRMs from retinas and optic nerves from early stages of the disease before evidence of neuronal cell loss. Most of the PrPres remained associated with lipid rafts throughout different stages in disease progression. In contrast to PrPres, caveolin 1 and synaptophysin in retina and optic nerves shifted to non-DRM fractions during the course of scrapie infection. The accumulation of PrPres in DRMs was not associated with a general alteration in their composition, because no change in the total protein distribution across the sucrose gradient or in the flotation characteristics of the glycosphingolipid GM1 or Thy-1 were observed until advanced stages of the disease. However, an increase in total cholesterol levels was observed in optic nerve and retinas. Only during late stages of the disease was a decrease in the number of neuronal cell bodies observed, suggesting that synaptic abnormalities are the earliest sign of neuronal dysfunction that ultimately results in neuronal death. These results indicate that prion replication triggers an abnormal localization of caveolin 1 and synaptophysin, which in turn may alter neuronal function.