Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.
Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.
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DOI：
10.1038/s41598-023-51137-6
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发表时间：
2024-01-04
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
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家族性自主神经功能障碍 (FD) 是一种罕见的隐性神经发育疾病，由伸长乙酰转移酶复合物亚基 1 (ELP1) 基因剪接突变引起。这种突变导致 ELP1 蛋白的组织特异性减少，其中中枢神经系统和周围神经系统（分别为 CNS 和 PNS）的水平最低。由于感觉神经元和自主神经元的丧失，FD 患者表现出复杂的神经表型。疾病症状包括疼痛和温度感知减弱、肌张力反射受损或缺失、本体感觉性共济失调和进行性视网膜变性。虽然三七总皂苷参与 FD 发病机制已得到明确认识，但造成优先神经元丢失的潜在机制仍不清楚。在这项研究中，我们旨在通过对表型小鼠模型 TgFD9 的神经元组织进行全面的转录组分析来阐明 FD 的分子机制。 Elp1Δ20/flox。该小鼠重现了在对许多疾病表现进行建模时在患者中观察到的相同组织特异性 ELP1 错误剪接。 FD 和来自背根神经节 (DRG)、三叉神经节 (TG)、髓质 (MED)、皮质和脊髓 (SC) 的对照转录组的比较显示，PNS 中的差异表达基因 (DEG) 显着多于 CNS。然后，我们鉴定了紧密共表达且功能依赖于全长 ELP1 转录物水平的基因。这些基因被定义为 ELP1 剂量反应基因，与 DEG 结合产生组织特异性失调的 FD 特征基因和网络。在 PNS 网络中，我们观察到 Elp1 与参与 tRNA 合成的基因以及与胺代谢和突触信号传导相关的基因之间的直接联系。重要的是，PNS 组织中的转录组失调表现出与肽能伤害感受器和有髓感觉神经元相关的神经元亚型标记物的富集，已知这些神经元在 FD 中受到影响。总之，这项研究确定了 FD 病因学中关键的组织特异性基因网络，并为该疾病的分子基础提供了新的见解。
Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9; Elp1Δ20/flox. This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4.6
作者：
Cahill KM;Huo Z;Tseng GC;Logan RW;Seney ML
通讯作者：
Seney ML
影响因子：
4.3
作者：
Bauer, Fanelie;Hermand, Damien
通讯作者：
Hermand, Damien
DOI：
10.1073/pnas.1308596110
发表时间：
2013-11-12
影响因子：
11.1
作者：
George, Lynn;Chaverra, Marta;Lefcort, Frances
通讯作者：
Lefcort, Frances
影响因子：
46.9
作者：
Cortal, Akira;Martignetti, Loredana;Rausell, Antonio
通讯作者：
Rausell, Antonio