PDF(Pubmed)
Abstract：
Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. Here, we identify a neuroprotective role for NG2 glia against prion toxicity. NG2 glia were activated after prion infection in cerebellar organotypic cultured slices (COCS) and in brains of prion-inoculated mice. In both model systems, depletion of NG2 glia exacerbated prion-induced neurodegeneration and accelerated prion pathology. Loss of NG2 glia enhanced the biosynthesis of prostaglandin E2 (PGE2) by microglia, which augmented prion neurotoxicity through binding to the EP4 receptor. Pharmacological or genetic inhibition of PGE2 biosynthesis attenuated prion-induced neurodegeneration in COCS and mice, reduced the enhanced neurodegeneration in NG2-glia-depleted COCS after prion infection, and dampened the acceleration of prion disease in NG2-glia-depleted mice. These data unveil a non-cell-autonomous interaction between NG2 glia and microglia in prion disease and suggest that PGE2 signaling may represent an actionable target against prion diseases.
摘要：
少突胶质细胞谱系细胞，包括NG2胶质细胞,经历各种神经退行性疾病的显著变化。这里,我们确定了NG2神经胶质对朊病毒毒性的神经保护作用。朊病毒感染后，小脑器官型培养切片（COCS）和朊病毒接种小鼠的大脑中的NG2胶质细胞被激活。在这两个模型系统中，NG2神经胶质的耗竭加剧了朊病毒诱导的神经变性并加速了朊病毒病理。NG2胶质细胞的缺失增强了小胶质细胞对前列腺素E2(PGE2)的生物合成,通过与EP4受体结合增强朊病毒的神经毒性。PGE2生物合成的药理学或遗传学抑制减弱了COCS和小鼠的朊病毒诱导的神经变性，减少NG2-神经胶质细胞耗竭COCS增强的神经变性感染后，并抑制了NG2-胶质细胞耗竭小鼠中朊病毒病的加速。这些数据揭示了朊病毒疾病中NG2神经胶质和小胶质细胞之间的非细胞自主相互作用，并表明PGE2信号传导可能代表了针对朊病毒疾病的可行靶标。
