Cytosolic prion protein toxicity is independent of cellular prion protein expression and prion propagation
Cytosolic prion protein toxicity is independent of cellular prion protein expression and prion propagation
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DOI：
10.1128/jvi.02157-06
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发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Mastrianni, James A.
中科院分区：
文献类型：
--
作者：
Norstrom, Eric M.;Ciaccio, Mark F.;Mastrianni, James A.
朊病毒病是由朊病毒蛋白（PrP）的构象异构体（一种宿主编码的细胞表面唾液酸糖蛋白）引起的传染性神经退行性疾病。最近的证据表明，胞浆部分的PrP（cyPrP）的功能，无论是作为一个启动因子或毒性元素的朊病毒疾病。当在培养的细胞中表达时，cyPrP获得PrP（PrPSc）的感染性构象的性质，包括不溶性、蛋白酶抗性、聚集和毒性。共表达cyPrP和PrPC的转基因小鼠（2D 1和1D 4系）表现出局灶性小脑萎缩、抓挠行为和步态异常，提示朊病毒疾病，尽管它们缺乏蛋白酶抗性PrP。为了确定PrPC的共表达对于这些小鼠的表型是否是必需的或抑制的，我们将Tg 1D 4（Prnp（+/+））小鼠与PrP消融小鼠（TgPrnp（o/o））杂交以产生Tg 1D 4（Prnp（o/o））小鼠，并跟踪疾病和病理表型的发展。我们发现Tg 1D 4（Prnp（+/+））和Tg 1D 4（Prnp（o/o））小鼠之间的症状发作或疾病的临床或病理表型没有差异，表明cyPrP和PrPC在疾病状态下独立发挥作用。此外，Tg 1D 4（Prnp（o/o））小鼠对小鼠适应性瘙痒病（RML）的攻击具有抗性，表明cyPrP无法接近PrPSc。我们的结论是，疾病表型和细胞毒性与表达的cyPrP是独立的PrPC和典型的朊病毒疾病的产生。
Prion diseases are transmissible neurodegenerative diseases caused by a conformational isoform of the prion protein (PrP), a host-encoded cell surface sialoglycoprotein. Recent evidence suggests a cytosolic fraction of PrP (cyPrP) functions either as an initiating factor or toxic element of prion disease. When expressed in cultured cells, cyPrP acquires properties of the infectious conformation of PrP (PrPSc), including insolubility, protease resistance, aggregation, and toxicity. Transgenic mice (2D1 and 1D4 lines) that coexpress cyPrP and PrPC exhibit focal cerebellar atrophy, scratching behavior, and gait abnormalities suggestive of prion disease, although they lack protease-resistant PrP. To determine if the coexpression of PrPC is necessary or inhibitory to the phenotype of these mice, we crossed Tg1D4(Prnp(+/+)) mice with PrP-ablated mice (TgPrnp(o/o)) to generate Tg1D4(Prnp(o/o)) mice and followed the development of disease and pathological phenotype. We found no difference in the onset of symptoms or the clinical or pathological phenotype of disease between Tg1D4(Prnp(+/+)) and Tg1D4(Prnp(o/o)) mice, suggesting that cyPrP and PrPC function independently in the disease state. Additionally, Tg1D4(Prnp(o/o)) mice were resistant to challenge with mouse-adapted scrapie (RML), suggesting cyPrP is inaccessible to PrPSc. We conclude that disease phenotype and cellular toxicity associated with the expression of cyPrP are independent of PrPC and the generation of typical prion disease.