Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions
Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions
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TDP-43 病理学对额颞叶变性的转录组分析揭示了多个大脑区域的细胞改变
DOI：
10.1101/2021.10.06.21264635
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hasan R
中科院分区：
文献类型：
--
作者：
Hasan R
额颞叶变性（FTLD）是一组影响大脑额叶和颞叶的异质性神经退行性疾病。 RNA 结合蛋白 TDP-43 的核丢失和细胞质聚集代表了主要的 FTLD 病理学，称为 FTLD-TDP。迄今为止，由于对疾病发展的分子机制的了解不完全，FTLD-TDP 尚无有效的治疗方法。在这里，我们比较了 28 名对照者和 30 名 FTLD-TDP 患者的额叶皮层、颞叶皮层和小脑的死后组织 RNA-seq 转录组，以描绘细胞类型组成、基因表达和转录本使用的变化。我们观察到大脑所有三个区域的神经元标记物均下调，同时小胶质细胞、星形胶质细胞、少突胶质细胞以及内皮细胞和周细胞上调，表明免疫激活和脉管系统内发生了变化。我们使用神经病理学萎缩评分验证了对神经元损失的估计，并表明皮质中的神经元损失主要归因于兴奋性神经元，并且小胶质细胞和内皮细胞表达的增加与神经元损失高度相关。我们所有的分析都表明小脑在 FTLD-TDP 的神经退行性过程中发挥着重要作用。总而言之，我们的数据提供了基因表达改变的详细情况，有助于阐明 FTLD 的相关疾病机制。
Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared postmortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex, and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.
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