Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.
Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.
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PRPSC在神经元和神经胶质上的积累中的pr菌菌株差异与神经炎症基因的相似表达谱有关：三个prion菌株的比较。
DOI：
10.1371/journal.ppat.1005551
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Chesebro B
中科院分区：
文献类型：
--
作者：
Carroll JA;Striebel JF;Rangel A;Woods T;Phillips K;Peterson KE;Race B;Chesebro B
宿主蛋白质的错误折叠和聚集是神经退行性疾病（包括阿尔茨海默病、帕金森病、额颞叶痴呆和朊病毒病）发病机制的重要特征。在所有这些疾病中，错误折叠的蛋白质通过涉及种子聚合的机制增加量。在朊病毒疾病中，宿主朊病毒蛋白被错误折叠以形成致病性蛋白酶抗性形式PrPSc，其在CNS中的神经元、星形胶质细胞和小胶质细胞中积累。在这里使用双染色免疫组化，我们比较了细胞特异性的PrPSc积累在早期临床前时间感染后使用三种小鼠瘙痒症菌株，不同的大脑区域病理学。来自每种菌株的PrPSc具有不同的细胞特异性模式。菌株22 L主要与星形胶质细胞相关，而菌株ME 7主要与神经元和神经胶质细胞相关。在丘脑和皮层中，RML与22 L相似，但在黑质中，RML与ME 7相似。利用临床前丘脑mRNA定量研究了参与神经炎症的90个基因的表达。令人惊讶的是，尽管PrPSc积累的细胞差异，上调基因的模式是相似的所有三个菌株，观察到的小差异与早期疾病克里思的变化。基因上调与空泡病理学或临床体征之前的早期疾病中检测到的星形胶质细胞和小胶质细胞的活化相关。有趣的是，羊瘙痒症中上调基因的分布与两种急性病毒性CNS疾病（长曲棍球病毒和BE多效性Friend逆转录病毒）中观察到的明显不同，这两种疾病具有与朊病毒感染小鼠相似的反应性胶质增生水平。错误折叠的蛋白质聚集体在脑中的积累是在包括朊病毒病、阿尔茨海默病和帕金森病的几种神经退行性疾病中看到的损伤的共同特征。在目前的工作中，三种朊病毒疾病的不同积累的疾病相关朊病毒蛋白（PrPSc）的神经元和星形胶质细胞。这些模式在接种后40-60天首先在丘脑中检测到。这与胶质增生和PrPSc沉积的初始检测相吻合，但远远领先于临床体征或海绵状病理。尽管细胞PrPSc沉积模式不同，但这三种菌株在神经炎症反应和神经胶质增生过程中具有相似的大量基因表达模式。然而，羊瘙痒病的基因上调与两种神经毒性病毒性疾病的基因上调明显不同，后者也有丰富的神经胶质反应，与朊病毒感染相似。
Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice. Accumulation of aggregates of misfolded protein in brain is a common feature of the damage seen in several neurodegenerative diseases including prion disease, Alzheimer’s disease and Parkinson’s disease. In the present work three strains of prion disease differed in accumulation of the disease-associated prion protein (PrPSc) on neurons and astroglial cells. These patterns were first detectable in the thalamus at 40–60 days after inoculation. This coincided with initial detection of gliosis and PrPSc deposition, but was far in advance of clinical signs or spongiform pathology. In spite of the different patterns of cellular PrPSc deposition, these three strains had similar patterns of expression of a large number of genes known to be active during neuroinflammatory responses and gliosis. However, the gene upregulation in scrapie differed markedly from that seen in two neurovirulent viral diseases, which also had abundant glial responses similar to those observed with prion infection.