Discrimination of Prion Strain Targeting in the Central Nervous System via Reactive Astrocyte Heterogeneity in CD44 Expression
Discrimination of Prion Strain Targeting in the Central Nervous System via Reactive Astrocyte Heterogeneity in CD44 Expression
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DOI：
10.3389/fncel.2019.00411
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发表时间：
2019-09-10
影响因子：
5.3
通讯作者：
Mabbott, Neil A.
中科院分区：
文献类型：
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作者：
Bradford, Barry M.;Wijaya, Christianus A. W.;Mabbott, Neil A.
朊病毒疾病或传染性海绵状脑病是致命的、进行性的、神经退行性的、蛋白质错误折叠的疾病。朊病毒疾病可自发产生、遗传或通过感染获得，影响包括人类在内的多种哺乳动物物种。中枢神经系统（CNS）的朊病毒感染引起广泛的神经病理学，包括宿主朊病毒蛋白错误折叠的异常积聚，空泡改变导致CNS组织海绵状外观，神经变性和反应性胶质反应。存在许多不同的朊病毒毒株，这些毒株可以根据疾病持续时间、临床体征以及不同脑区神经病理学的靶向和分布而有所不同。反应性星形胶质细胞是朊病毒病影响中枢神经系统的一个显著特征，其表现为明显的形态改变和胶质原纤维酸性蛋白（GFAP）的上调。CD44抗原是一种跨膜糖蛋白，参与细胞间相互作用、细胞粘附和迁移。在这里，我们发现CD44在朊病毒靶向的中枢神经系统区域的反应性星形细胞亚群中也高度表达。CD44差异上调所显示的星形胶质细胞异质性与疾病临床前阶段最早的神经病理改变一致，不受感染途径的影响。本研究比较了15种不同的朊病毒毒株传播给不同朊病毒蛋白（Prnp）基因型背景小鼠的脑组织中CD44的表达和分布。我们的数据显示，每种朊病毒制剂菌株和宿主Prnp基因型组合在海马中观察到的CD44上调模式是独特的。许多小鼠适应的朊病毒毒株和宿主先前已经根据海绵状病理分布模式或脑内错误折叠的PrP沉积来表征。我们的数据表明，CD44的表达也提供了一个可靠的朊病毒感染的鉴别标记，其动态范围比错误折叠的朊病毒蛋白沉积更大，有助于菌株鉴定。总之，我们的数据显示CD44是一种新的标志物，可用于检测中枢神经系统朊病毒疾病期间的反应性星形细胞异质性，并增强对不同朊病毒菌株的识别。
Prion diseases or transmissible spongiform encephalopathies are fatal, progressive, neurodegenerative, protein-misfolding disorders. Prion diseases may arise spontaneously, be inherited genetically or be acquired by infection and affect a variety of mammalian species including humans. Prion infections in the central nervous system (CNS) cause extensive neuropathology, including abnormal accumulations of misfolded host prion protein, vacuolar change resulting in sponge-like (spongiform) appearance of CNS tissue, neurodegeneration and reactive glial responses. Many different prion agent strains exist and these can differ based on disease duration, clinical signs and the targeting and distribution of the neuropathology in distinct brain areas. Reactive astrocytes are a prominent feature in the prion disease affected CNS as revealed by distinct morphological changes and upregulation of glial fibrillary acidic protein (GFAP). The CD44 antigen is a transmembrane glycoprotein involved in cell-cell interactions, cell adhesion and migration. Here we show that CD44 is also highly expressed in a subset of reactive astrocytes in regions of the CNS targeted by prions. Astrocyte heterogeneity revealed by differential CD44 upregulation occurs coincident with the earliest neuropathological changes during the pre-clinical phase of disease, and is not affected by the route of infection. The expression and distribution of CD44 was compared in brains from a large collection of 15 distinct prion agent strains transmitted to mice of different prion protein (Prnp) genotype backgrounds. Our data show that the pattern of CD44 upregulation observed in the hippocampus in each prion agent strain and host Prnp genotype combination was unique. Many mouse-adapted prion strains and hosts have previously been characterized based on the pattern of the distribution of the spongiform pathology or the misfolded PrP deposition within the brain. Our data show that CD44 expression also provides a reliable discriminatory marker of prion infection with a greater dynamic range than misfolded prion protein deposition, aiding strain identification. Together, our data reveal CD44 as a novel marker to detect reactive astrocyte heterogeneity during CNS prion disease and for enhanced identification of distinct prion agent strains.