Raphe and ventrolateral medulla proteomics in sudden unexplained death in childhood with febrile seizure history

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2024-11-28 DOI:10.1007/s00401-024-02832-9

Dominique F. Leitner, Christopher William, Arline Faustin, Evgeny Kanshin, Matija Snuderl, Declan McGuone, Thomas Wisniewski, Beatrix Ueberheide, Laura Gould, Orrin Devinsky

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引用次数: 0

Abstract

Sudden unexplained death in childhood (SUDC) is death of a child ≥ 12 months old that is unexplained after autopsy and detailed analyses. Among SUDC cases, ~ 30% have febrile seizure (FS) history, versus 2–5% in the general population. SUDC cases share features with sudden unexpected death in epilepsy (SUDEP) and sudden infant death syndrome (SIDS), in which brainstem autonomic dysfunction is implicated. To understand whether brainstem protein changes are associated with FS history in SUDC, we performed label-free quantitative mass spectrometry on microdissected midbrain dorsal raphe, medullary raphe, and the ventrolateral medulla (n = 8 SUDC-noFS, n = 11 SUDC-FS). Differential expression analysis between SUDC-FS and SUDC-noFS at p < 0.05 identified 178 altered proteins in dorsal raphe, 344 in medullary raphe, and 100 in the ventrolateral medulla. These proteins were most significantly associated with increased eukaryotic translation initiation (p = 3.09 × 10^–7, z = 1.00), eukaryotic translation elongation (p = 6.31 × 10^–49, z = 6.01), and coagulation system (p = 1.32 × 10^–5, z = 1.00). The medullary raphe had the strongest enrichment for altered signaling pathways, including with comparisons to three other brain regions previously analyzed (frontal cortex, hippocampal dentate gyrus, cornu ammonus). Immunofluorescent tissue analysis of serotonin receptors identified 2.1-fold increased 5HT2A in the medullary raphe of SUDC-FS (p = 0.025). Weighted gene correlation network analysis (WGCNA) of case history indicated that longer FS history duration significantly correlated with protein levels in the medullary raphe and ventrolateral medulla; the most significant gene ontology biological processes were decreased cellular respiration (p = 9.8 × 10^–5, corr = − 0.80) in medullary raphe and decreased synaptic vesicle cycle (p = 1.60 × 10^–7, corr = − 0.90) in the ventrolateral medulla. Overall, FS in SUDC was associated with more protein differences in the medullary raphe and was related with increased translation-related signaling pathways. Future studies should assess whether these changes result from FS or may in some way predispose to FS or SUDC.

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有发热性癫痫发作史的儿童不明原因猝死的边和室外侧延髓蛋白质组学研究

儿童不明原因猝死（SUDC）是指年龄≥12个月的儿童在尸检和详细分析后不明原因死亡。在SUDC病例中，约30%有发热性癫痫发作（FS）病史，而在普通人群中这一比例仅为2%-5%。SUDC病例与癫痫意外猝死（SUDEP）和婴儿猝死综合征（SIDS）有共同特征，其中脑干自主神经功能障碍与这两种病症有牵连。为了解脑干蛋白变化是否与 SUDC 的 FS 病史有关，我们对显微解剖的中脑背侧剑突、髓质剑突和室外侧髓质（n = 8 SUDC-noFS，n = 11 SUDC-FS）进行了无标记定量质谱分析。在 p < 0.05 时，对 SUDC-FS 和 SUDC-noFS 进行差异表达分析，发现背侧急腹症有 178 个蛋白质发生了改变，髓质急腹症有 344 个，外侧髓质有 100 个。这些蛋白质与真核翻译起始（p = 3.09 × 10-7，z = 1.00）、真核翻译伸长（p = 6.31 × 10-49，z = 6.01）和凝血系统（p = 1.32 × 10-5，z = 1.00）的增加关系最为密切。与之前分析过的其他三个脑区（额叶皮层、海马齿状回、胼胝体）相比，延髓脑区信号通路改变的富集程度最高。对血清素受体的免疫荧光组织分析发现，SUDC-FS 髓质剑突中的 5HT2A 增加了 2.1 倍（p = 0.025）。病史的加权基因相关网络分析（WGCNA）表明，较长的FS病史与延髓急腹症和外侧髓质的蛋白质水平显著相关；最显著的基因本体生物学过程是延髓急腹症的细胞呼吸减少（p = 9.8 × 10-5，corr = - 0.80）和外侧髓质的突触小泡周期减少（p = 1.60 × 10-7，corr = - 0.90）。总体而言，SUDC 中的 FS 与延髓剑突中更多的蛋白质差异有关，并与翻译相关信号通路的增加有关。未来的研究应评估这些变化是由 FS 引起的，还是可能以某种方式导致 FS 或 SUDC。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.