Ganglioside Synthase Knockout Reduces Prion Disease Incubation Time in Mouse Models
Ganglioside Synthase Knockout Reduces Prion Disease Incubation Time in Mouse Models
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神经节苷脂合酶敲除可缩短小鼠模型中朊病毒病的潜伏时间
DOI：
10.1016/j.ajpath.2018.11.009
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Miyoshi Ichiro
中科院分区：
文献类型：
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作者：
Kobayashi Atsushi;Qi Zechen;Shimazaki Taishi;Munesue Yoshiko;Miyamoto Tomomi;Isoda Norikazu;Sawa Hirofumi;Aoshima Keisuke;Kimura Takashi;Mohri Shirou;Kitamoto Tetsuyuki;Yamashita Tadashi;Miyoshi Ichiro
朊病毒蛋白的异常和正常亚型定位于抗洗涤剂的膜微区，脂筏，对于构象转换是重要的。脂筏富含含唾液酸的鞘糖脂（即神经节苷脂）。脂筏中神经节苷脂组成的改变可以影响脂筏相关蛋白的定位。为了研究神经节苷脂在朊病毒疾病发病机制中的作用，我们使用神经节苷脂合酶基因（即GD 2/GM 2合酶、GD 3合酶或GM 3合酶）切除的各种敲除小鼠品系，对瘙痒症朊病毒株钱德勒和Gerstmann-Sträussler-Scheinker综合征朊病毒株Fukuoka-1进行了脑内传播研究。用钱德勒品系攻击后，GD 2/GM 2合酶敲除小鼠显示孵育时间减少20%，脑中朊病毒蛋白沉积减少，神经胶质反应减弱，朊病毒蛋白定位于脂筏减少。这些结果提高了神经节苷脂可能有一个重要的作用，在朊病毒疾病的发病机制，通过影响朊病毒蛋白的定位脂筏。
Localization of the abnormal and normal isoforms of prion proteins to detergent-resistant membrane microdomains, lipid rafts, is important for the conformational conversion. Lipid rafts are enriched in sialic acid–containing glycosphingolipids (namely, gangliosides). Alteration in the ganglioside composition of lipid rafts can affect the localization of lipid raft–associated proteins. To investigate the role of gangliosides in the pathogenesis of prion diseases, we performed intracerebral transmission study of a scrapie prion strain Chandler and a Gerstmann-Sträussler-Scheinker syndrome prion strain Fukuoka-1 using various knockout mouse strains ablated with ganglioside synthase gene (ie, GD2/GM2 synthase, GD3 synthase, or GM3 synthase). After challenge with the Chandler strain, GD2/GM2 synthase knockout mice showed 20% reduction of incubation time, reduced prion protein deposition in the brain with attenuated glial reactions, and reduced localization of prion proteins to lipid rafts. These results raise the possibility that the gangliosides may have an important role in prion disease pathogenesis by affecting the localization of prion proteins to lipid rafts.