Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice. Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite appearing normal. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated reduced synthesis of ribosomal and mitochondrial components, 2) glutamatergic neurons showed increased expression of cytoskeletal genes, and 3) GABAergic neurons revealed reduced expression of circadian rhythm genes. These data demonstrate that early translatome responses to neurodegeneration emerge prior to conventional markers of disease and are cell type-specific. Therapeutic strategies may need to target multiple pathways in specific populations of cells, early in disease. Overall design: RiboTag translatome profiling data demonstrating that early translatome responses to neurodegeneration emerge prior to other signs of disease and are unique to different cell types.

选择性易损性是神经退行性疾病（NDs）的一类难以阐释的特征：广泛表达的蛋白质会在特定细胞类型与脑区引发病变。本研究通过小鼠体内的核糖体标签（RiboTag）技术，对五种神经细胞亚型在感染获得性朊病毒病（PrD）后的翻译应答进行了检测。研究基于纵向脑电图（EEG）结果选取疾病发作前与疾病发作两个时间节点：脑电图显示，在朊病毒注射后10至18周期间，小鼠的θ波功率呈渐进式升高，这一特征与人类朊病毒病的临床表型相似。在以θ波功率显著升高与组织病理学病变为标志的疾病发作节点，尽管小鼠外观仍表现正常，但其五种细胞类型的翻译组（translatome）均出现了显著变化。值得注意的是，在脑电图与神经病理学改变出现前的疾病发作前阶段，我们发现：星形胶质细胞的翻译组显示核糖体与线粒体组分的合成水平降低；谷氨酸能神经元的细胞骨架基因表达量升高；γ-氨基丁酸能神经元的昼夜节律相关基因表达量降低。上述数据表明，针对神经退行性变的早期翻译组应答，会先于常规疾病标志物出现，且呈现细胞类型特异性。在疾病早期阶段，治疗策略可能需要靶向特定细胞群中的多条通路。实验整体设计：本研究通过核糖体标签翻译组谱分析（RiboTag translatome profiling）数据证实，针对神经退行性变的早期翻译组应答，会先于其他疾病征象出现，且在不同细胞类型中表现各异。