A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP.
A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP.
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DOI：
10.1523/jneurosci.2542-09.2009
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发表时间：
2009-08-12
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影响因子：
--
通讯作者：
Mastrianni JA
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文献类型：
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作者：
Yang W;Cook J;Rassbach B;Lemus A;DeArmond SJ;Mastrianni JA
Gerstmann-Sträussler-Scheinker综合征（GSS）是一种遗传性朊病毒疾病，临床表现为进行性共济失调和痴呆，组织病理学表现为在中枢神经系统，特别是小脑内存在朊蛋白（PrP）淀粉样斑块。PrP基因（PRNP）的几种突变与GSS有关，但只有P102L突变在转基因（Tg）小鼠中得到了令人信服的模型。为了确定其他突变是否携带特定的GSS表型信息，我们构建了Tg小鼠，这些小鼠表达PrP，携带GSS相关的A117V突变的小鼠同源物。Tg（A116V）小鼠表达内源性PrP水平的约6倍，约140天发生进行性共济失调，约170天死亡。与传染性克雅氏病（CJD）小鼠模型相比，Tg（A116V）小鼠的共济失调更为突出，病程延长，与人类疾病相似。神经病理学表现为轻度分散空泡化和突出的，主要是小脑局限性的，由全长PrPA116V组成的硫黄素S阳性PrP斑块。在一些小鼠中，更突出的空泡化或PrP斑块的非小脑分布是明显的，这表明在表型上存在一些变异性。从Tg（A116V）小鼠和人GSS（A117V）中提取的PrP的生物物理性质显示，不溶性PrP的比例相似，且具有弱蛋白酶抗性~13 kDa的跨中PrP片段，这在CJD中没有观察到。总体而言，Tg（A116V）小鼠再现了GSS（A117V）不同于CJD的许多临床病理特征，支持PrPA116V携带特异性表型信息。它们在组织病理学上偶尔表现出的变化可能为人类GSS（A117V）的类似观察提供了线索。
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a genetic prion disease typified clinically by the development of progressive ataxia and dementia, and histopathologically by the presence of prion protein (PrP) amyloid plaques in the CNS, especially within the cerebellum. Several mutations of the PrP gene (PRNP) are associated with GSS, but only the P102L mutation has been convincingly modeled in transgenic (Tg) mice. To determine if other mutations carry specific GSS phenotypic information, we constructed Tg mice that express PrP carrying the mouse homolog of the GSS-associated A117V mutation. Tg(A116V) mice express ~6 times the endogenous levels of PrP, develop progressive ataxia by ~140 days, and death by ~170 days. Compared with a mouse model of transmissible Creutzfeldt-Jakob disease (CJD), the ataxia of Tg(A116V) mice is more prominent, and the course of disease is more protracted, paralleling that observed in human disease. Neuropathology includes mild scattered vacuolation and prominent, mainly cerebellar localized, thioflavin S positive PrP plaques comprised of full length PrPA116V. In some mice, more prominent vacuolation or a non-cerebellar distribution of PrP plaques was evident, suggesting some variability in phenotype. The biophysical properties of PrP from Tg(A116V) mice and human GSS(A117V) revealed a similarly low fraction of insoluble PrP and a weakly protease-resistant ~13 kDa mid-span PrP fragment, not observed in CJD. Overall, Tg(A116V) mice recapitulate many clinicopathologic features of GSS(A117V) that are distinct from CJD, supporting PrPA116V to carry specific phenotypic information. The occasional variation in histopathology they exhibit may shed light on a similar observation in human GSS(A117V).