A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome
A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome
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DOI：
10.1093/hmg/ddq379
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发表时间：
2010-11-15
影响因子：
3.5
通讯作者：
Kim, Yong-Sun
中科院分区：
文献类型：
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作者：
Choi, Jin-Kyu;Jeon, Yong-Chul;Kim, Yong-Sun
我们通过表达在残基 101 处具有亮氨酸取代的小鼠朊病毒蛋白 (PrP) (MoPrPP101L) 建立了 Gerstmann-Straussler-Scheinker (GSS) 综合征的果蝇模型。表达 MoPrPP101L 但不表达野生型 MoPrP (MoPrP3F4) 的果蝇在攀爬能力和早期死亡方面表现出严重缺陷。果蝇中表达的 MoPrPP101L 被差异糖基化，位于突触末端，主要以沉积物形式存在于成人大脑中。我们发现 MoPrPP101L 果蝇的行为缺陷和早期死亡并不是由于 Caspase 3 依赖性程序性细胞死亡信号传导所致。此外，我们发现 MoPrPP101L 果蝇幼虫神经肌肉接头中的 1 型谷氨酸突触按钮显示卫星突触按钮数量显着增加。此外，MoPrPP101L 果蝇中 Bruchpilot 和 Discs 的数量显着减少。与年龄匹配的对照小鼠相比，感染瘙痒症的小鼠大脑中的 ELKS（一种活性区域基质标记物）显着降低。因此，分子水平上活性区结构的改变可能与果蝇和羊痒病感染小鼠 GSS 综合征的发病机制有关。
We have established a Drosophila model of Gerstmann-Straussler-Scheinker (GSS) syndrome by expressing mouse prion protein (PrP) having leucine substitution at residue 101 (MoPrPP101L). Flies expressing MoPrPP101L, but not wild-type MoPrP (MoPrP3F4), showed severe defects in climbing ability and early death. Expressed MoPrPP101L in Drosophila was differentially glycosylated, localized at the synaptic terminals and mainly present as deposits in adult brains. We found that behavioral defects and early death of MoPrPP101L flies were not due to Caspase 3-dependent programmed cell death signaling. In addition, we found that Type 1 glutamatergic synaptic boutons in larval neuromuscular junctions of MoPrPP101L flies showed significantly increased numbers of satellite synaptic boutons. Furthermore, the amount of Bruchpilot and Discs large in MoPrPP101L flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS, an active zone matrix marker compared with those of age-matched control mice. Thus, altered active zone structures at the molecular level may be involved in the pathogenesis of GSS syndrome in Drosophila and scrapie-infected mice.