Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations.
Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations.
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DOI：
10.1093/brain/awab437
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发表时间：
2022-07-29
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额颞叶退行性变伴TDP-43夹杂物（FTLD-TDP）是一种复杂的异质性神经退行性疾病，其机制尚不清楚。为了探索FTLD-TDP潜在的转录变化，我们对66名遗传原因不明的FTLD-TDP患者、24名GRN突变的FTLD-TDP患者和24名对照参与者进行了RNA测序。使用主成分分析，层次聚类，差异表达和共表达网络分析，我们发现，GRN突变携带者和FTLD-TDP-A患者没有一个已知的突变共享一个共同的转录签名，是独立的GRN功能丧失。合并两组后，与对照组相比差异表达和共表达分析揭示了与免疫应答、突触传递、RNA代谢、血管生成和囊泡介导的运输相关的过程的改变。数据的去卷积突出了FTLD-TDP-A和GRN突变携带者中相似的强烈细胞改变，NSF在两组中都是潜在的重要参与者。我们提出了几种潜在的药物途径，如GABA能，GDNF和鞘脂途径。我们的研究结果强调了新的疾病机制，并强烈表明GRN突变携带者中受影响的途径延伸到GRN之外，并导致遗传上无法解释的FTLD-TDP-A形式。为了更好地了解FTLD的潜在疾病过程，Pottier等人比较了患者与健康对照的基因表达。具有GRN突变的患者与具有类似脑病理的遗传原因不明的患者具有相似的转录谱，在几个潜在的药物途径中具有改变。
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A. To better understand the disease processes underlying FTLD, Pottier et al. compare gene expression in patients versus healthy controls. Patients with GRN mutations have a similar transcriptional profile to genetically unexplained patients with similar brain pathology, with alterations in several potentially druggable pathways.
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影响因子：
64.8
作者：
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