Mutant prion protein D202N associated with familial prion disease is retained in the endoplasmic reticulum and forms 'Curly' intracellular aggregates
Mutant prion protein D202N associated with familial prion disease is retained in the endoplasmic reticulum and forms 'Curly' intracellular aggregates
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DOI：
10.1007/s12031-007-0023-6
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发表时间：
2007-01-01
影响因子：
3.1
通讯作者：
Singh, Neena
中科院分区：
文献类型：
--
作者：
Gu, Yaping;Verghese, Susarnma;Singh, Neena
传染性海绵状脑病是人类和动物的致命性神经退行性疾病，具有家族性、散发性和传染性。人类的家族性疾病包括Gerstmann-Straussler-Scheinker病（GSS）、家族性Creutzfeldt-Jakob病（CJD）和致命的家族性失眠症，并且由朊病毒蛋白基因中的点突变引起。虽然家族性病例中的神经毒性被认为是由突变型朊病毒蛋白（PrP）构象自发变化为致病性PrP-羊瘙痒病（PrPSc）形式引起的，但新出现的证据表明并非如此。我们研究了突变型PrP D202 N（Prp（202 N））在细胞模型中的加工和代谢，以阐明细胞毒性的可能机制。在这份报告中，我们证明，Prp（202 N）在人神经母细胞瘤细胞中表达的合成后未能达到成熟的构象，并在内质网中积累为“卷曲”的聚集体。此外，prp（202 N）细胞显示出对自由基的敏感性增加，表明神经元对氧化损伤的易感性可能是在PrP D202 N突变导致的GSS病例中观察到的神经毒性的原因。
Transmissible Spongiform Encephalopathies are fatal neurodegenerative disorders of humans and animals that are familial, sporadic, and infectious in nature. Familial disorders of humans include Gerstmann-StrausslerScheinker disease (GSS), familial Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia, and result from point mutations in the prion protein gene. Although neurotoxicity in familial cases is believed to result from a spontaneous change in conformation of mutant prion protein (PrP) to the pathogenic PrP-scrapie (PrPSc) form, emerging evidence indicates otherwise. We have investigated the processing and metabolism of mutant PrP D202N (Prp(202N)) in cell models to elucidate possible mechanisms of cytotoxicity. In this report, we demonstrate that Prp(202N) expressed in human neuroblastoma cells fails to achieve a mature conformation following synthesis and accumulates in the endoplasmic reticulum as 'curly' aggregates. In addition, prp(202N) cells show increased sensitivity to free radicals, indicating that neuronal susceptibility to oxidative damage may account for the neurotoxicity observed in cases of GSS resulting from PrP D202N mutation.