Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells
Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells
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DOI：
10.1523/jneurosci.0653-05.2005
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发表时间：
2005-05-25
影响因子：
5.3
通讯作者：
Caughey, B
中科院分区：
文献类型：
--
作者：
Magalhaes, AC;Baron, GS;Caughey, B
神经系统的侵袭和感染的神经元扩散是传染性海绵状脑病或普恩病毒疾病发病机制中的关键步骤，但知之甚少。用荧光标记的PrP-RES感染原代培养的小鼠神经细胞(SN56)和成年仓鼠皮质神经元，研究PrP-RES在神经细胞内摄取和转运感染PrP-RES的途径。在建立持续的瘙痒病感染的同时，SN56细胞将PrP-res聚集体内化成对晚期内小体和/或溶酶体标记物阳性的小泡，而不是突触、早期内吞细胞或RAFT来源的小泡。然后，内化的PrP-Res沿着轴突运输到与其他细胞的接触点。葡聚糖、阿尔茨海默病Aβ1-42纤维和非感染性重组PrP纤维也有类似的转运，表明PrP-res是通过相对非特异性的胞饮或跨细胞机制内化的。仓鼠皮质神经元也能内化和传播外源性PrP-Res。PrP基因敲除小鼠大脑培养的皮质神经元对外源性PrP-RES的类似转运表明，摄取和神经细胞转运不需要内源性细胞PrP的存在。这些实验可视化并表征了与Pron感染和神经细胞内运输相关的初始步骤。
Invasion of the nervous system and neuronal spread of infection are critical, but poorly understood, steps in the pathogenesis of transmissible spongiform encephalopathies or prion diseases. To characterize pathways for the uptake and intraneuronal trafficking of infectious, protease-resistant prion protein (PrP-res), fluorescent-labeled PrP-res was used to infect a neuronally derived murine cell line (SN56) and adult hamster cortical neurons in primary culture. Concurrent with the establishment of persistent scrapie infection, SN56 cells internalized PrP-res aggregates into vesicles positive for markers for late endosomes and/or lysosomes but not synaptic, early endocytic, or raft-derived vesicles. Internalized PrP-res was then transported along neurites to points of contact with other cells. Similar trafficking was observed with dextran, Alzheimer's A beta 1 - 42 fibrils and noninfectious recombinant PrP fibrils, suggesting that PrP-res is internalized by a relatively nonspecific pinocytosis or transcytosis mechanism. Hamster cortical neurons were also capable of internalizing and disseminating exogenous PrP-res. Similar trafficking of exogenous PrP-res by cortical neurons cultured from the brains of PrP knock-out mice showed that uptake and neuritic transport did not require the presence of endogenous cellular PrP. These experiments visualize and characterize the initial steps associated with prion infection and transport within neuronal cells.