Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities.
Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities.
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DOI：
10.1523/jneurosci.3109-08.2008
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发表时间：
2008-12-03
期刊：
影响因子：
--
通讯作者：
Harris DA
中科院分区：
文献类型：
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作者：
Chiesa R;Piccardo P;Biasini E;Ghetti B;Harris DA
导致朊病毒疾病神经变性的朊病毒蛋白（PrP）的神经毒性形式仍有待最终确定。大量证据表明 PrP 非感染性寡聚体在致病过程中的重要性。在本研究中，我们描述了 Tg(WT) 转基因小鼠品系，它们过表达野生型 PrP 约 5 倍或约 10 倍（分别取决于转基因阵列是半合子还是纯合子）。纯合子而非半合子 Tg(WT) 小鼠会出现一种自发性神经退行性疾病，其临床特征为震颤和麻痹。这两种小鼠的小脑分子层以及其他几个大脑区域都积累了大量的点状 PrP 沉积物，并且它们表现出异常增大的突触末端，并伴有膜结构的急剧增殖。 Tg(WT) 小鼠中过度表达的 PrP 组装成不溶性形式，具有轻度蛋白酶抗性，可被聚集特异性抗体识别，但在传播实验中不具有传染性。综上所述，我们的结果表明，野生型 PrP 的非感染性聚集体具有神经毒性，特别是对突触，并且它们表明朊病毒疾病和与蛋白质错误折叠相关的非传染性神经退行性疾病具有共同的致病机制。
The neurotoxic forms of the prion protein (PrP) that cause neurodegeneration in prion diseases remain to be conclusively identified. Considerable evidence points to the importance of non-infectious oligomers of PrP in the pathogenic process. In this study, we describe lines of Tg(WT) transgenic mice that over-express wild-type PrP by either ∼5-fold or ∼10-fold (depending on whether the transgene array is, respectively, hemizygous or homozygous). Homozygous but not hemizygous Tg(WT) mice develop a spontaneous neurodegenerative illness characterized clinically by tremor and paresis. Both kinds of mice accumulate large numbers of punctate PrP deposits in the molecular layer of the cerebellum as well as in several other brain regions, and they display abnormally enlarged synaptic terminals accompanied by a dramatic proliferation of membranous structures. The over-expressed PrP in Tg(WT) mice assembles into an insoluble form that is mildly protease-resistant and is recognizable by aggregation-specific antibodies, but that is not infectious in transmission experiments. Taken together, our results demonstrate that non-infectious aggregates of wild-type PrP are neurotoxic, particularly to synapses, and they suggest common pathogenic mechanisms shared by prion diseases and non-transmissible neurodegenerative disorders associated with protein misfolding.