The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease.
The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease.
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DOI：
10.1371/journal.ppat.1001317
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发表时间：
2011-03
期刊：
影响因子：
6.7
通讯作者：
Bartz JC
中科院分区：
文献类型：
--
作者：
Ayers JI;Schutt CR;Shikiya RA;Aguzzi A;Kincaid AE;Bartz JC
朊病毒株的特点是疾病结局的差异，最明显的是潜伏期和神经病理特征。虽然已经确定朊病毒蛋白的疾病特异性亚型PrPSc是感染因子的重要组成部分，但PrPSc特性与所导致疾病的生物学特征之间的菌株特异性关系尚不清楚。为了研究这种关系，我们检测了8种仓鼠适应朊病毒株的PrPSc的扩增效率和构象稳定性，并将其与由此产生的疾病潜伏期和PrPSc在神经元和胶质细胞中的加工进行了比较。我们发现，与长潜伏期菌株相比，短潜伏期菌株具有更高的PrPSc扩增效率和更高的PrPSc构象稳定性。在中枢神经系统中，短潜伏期菌株的特点是在神经元、星形胶质细胞和小胶质细胞的胞体中积累了n端截断的PrPSc，而长潜伏期菌株的PrPSc在神经元胞体中没有积累到可检测的水平，但在胶质细胞中检测到与短潜伏期菌株相似的PrPSc。这些结果与构象稳定性降低导致复制效率相应增加的假设不一致，并表明与神经元中PrPSc的直接复制相比，胶质细胞介导的神经变性导致更长的存活时间。朊病毒病是一组可影响包括人类在内的动物的传染性致死性神经退行性疾病。这种独特的感染因子是正常形式的朊病毒蛋白PrPC翻译后构象变化到感染形式的朊病毒蛋白PrPSc的结果。不同的感染因子菌株在单一宿主物种中导致不同的潜伏期和神经病理特征。这些疾病结果的菌株特异性差异可能是由于PrPSc的菌株特异性构象，尽管不同构象影响朊病毒菌株特性的机制尚不清楚。本研究的目的是探讨PrPSc的生化特性与8种仓鼠适应型朊病毒株相应神经病理特征的关系。我们的研究结果表明，与潜伏期相对较长的朊病毒菌株相比，潜伏期较短的菌株的PrPSc复制效率更高，构象更稳定，并且对神经元体细胞的清除更有抵抗力。这些结果表明，朊病毒疾病的进展受到神经元中PrPSc复制和清除之间平衡的影响。
Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrPSc, is an essential component of the infectious agent, the strain-specific relationship between PrPSc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrPSc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrPSc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrPSc amplification and higher PrPSc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrPSc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrPSc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrPSc in neurons. Prion diseases are a group of infectious fatal neurodegenerative diseases that affect animals including humans. This unique infectious agent is the result of a post-translational conformational change of the normal form of the prion protein, PrPC, to an infectious form of the prion protein, PrPSc. Different strains of the infectious agent result in characteristic incubation periods and neuropathological features within a single host species. These strain-specific differences in disease outcome are likely due to strain-specific conformations of PrPSc, though the mechanisms by which different conformation can affect prion strain properties are not understood. The aim of this study was to investigate the relationship between the biochemical properties of PrPSc to the corresponding neuropathological characteristics of eight hamster-adapted prion strains. Our findings indicate that PrPSc from short incubation period strains were more efficiently replicated, had a more stable conformation, and were observed to be more resistant to clearance from the soma of neurons compared to prion strains with a relatively long incubation period. These results suggest the progression of prion disease is influenced by the balance between replication and clearance of PrPSc in neurons.
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影响因子：
5.4
作者：
KASCSAK, RJ;RUBENSTEIN, R;DIRINGER, H
通讯作者：
DIRINGER, H
影响因子：
4.8
作者：
CHEN, SG;TEPLOW, DB;AUTILIOGAMBETTI, L
通讯作者：
AUTILIOGAMBETTI, L
影响因子：
6.7
作者：
Green, Kristi M.;Castilla, Joaquin;Telling, Glenn C.
通讯作者：
Telling, Glenn C.
影响因子：
16.2
作者：
DeArmond, SJ;Sánchez, H;Prusiner, SB
通讯作者：
Prusiner, SB
影响因子：
3.7
作者：
Bartz, JC;Marsh, RF;Aiken, JM
通讯作者：
Aiken, JM