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.

少突胶质细胞系细胞，包括 NG2 神经胶质细胞，在各种神经退行性疾病中经历显着变化。在这里，我们确定了 NG2 神经胶质细胞对抗朊病毒毒性的神经保护作用。小脑器官培养切片（COCS）和接种朊病毒的小鼠大脑中，NG2 神经胶质细胞在感染朊病毒后被激活。在这两个模型系统中，NG2 神经胶质细胞的消耗加剧了朊病毒诱导的神经变性并加速了朊病毒病理学。 NG2 胶质细胞的缺失增强了小胶质细胞前列腺素 E2 (PGE2) 的生物合成，从而通过与 EP4 受体结合增强了朊病毒的神经毒性。 PGE2生物合成的药理学或遗传抑制可减轻COCS和小鼠中朊病毒诱导的神经变性，减少朊病毒感染后NG2神经胶质细胞耗尽的COCS中增强的神经变性，并抑制NG2神经胶质细胞耗尽小鼠中朊病毒疾病的加速。这些数据揭示了朊病毒疾病中 NG2 胶质细胞和小胶质细胞之间的非细胞自主相互作用，并表明 PGE2 信号传导可能代表针对朊病毒疾病的可行靶点。