Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
Elife. 2020 Sep 22;9:e62911. doi: 10.7554/eLife.62911.
Prion diseases are caused by PrP, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrP causes a robust, reproducible and specific disease manifestation. Here, we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type-specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.
朊病毒疾病是由 PrP 引起的，PrP 是一种自我复制的病理性错误折叠的蛋白质，主要在大脑中发挥毒性作用。PrP 的给药会导致强壮、可重复和特异的疾病表现。在这里，我们应用了翻译核糖体亲和纯化和核糖体谱分析的组合，以鉴定在疾病进展过程中细胞类型特异性和全基因组范围内与朊病毒相关的生物学变化。患有严重神经症状的晚期患病小鼠在星形胶质细胞和小胶质细胞中表现出广泛的改变。令人惊讶的是，我们仅检测到神经元翻译谱的微小变化。朊病毒诱导的神经胶质细胞改变与其他神经退行性疾病中鉴定的改变重叠，表明类似的事件发生在广泛的病理范围内。我们的结果表明，神经胶质细胞内的异常翻译可能足以引起严重的神经症状，甚至可能是朊病毒疾病的主要驱动因素。
