Comprehensive Epilepsy Center, NYU Grossman School of Medicine, New York, NY, USA.
Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
Acta Neuropathol. 2024 Nov 28;148(1):76. doi: 10.1007/s00401-024-02832-9.
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, z = 1.00), eukaryotic translation elongation (p = 6.31 × 10, z = 6.01), and coagulation system (p = 1.32 × 10, 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, corr = - 0.80) in medullary raphe and decreased synaptic vesicle cycle (p = 1.60 × 10, 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.
儿童不明原因猝死 (SUDC) 是指在尸检和详细分析后无法解释的 12 个月以上儿童死亡。在 SUDC 病例中，约有 30%有热性惊厥 (FS) 病史，而普通人群中只有 2-5%。SUDC 病例与癫痫性猝倒 (SUDEP) 和婴儿猝死综合征 (SIDS) 具有共同特征，其中涉及脑干自主神经功能障碍。为了了解脑干蛋白变化是否与 SUDC 中的 FS 病史有关，我们对微分离的中脑背缝、延髓缝和腹外侧髓质 (n = 8 SUDC-noFS，n = 11 SUDC-FS) 进行了无标记定量质谱分析。SUDC-FS 和 SUDC-noFS 之间的差异表达分析，在 p < 0.05 时确定了背缝中有 178 个差异表达蛋白，延髓中有 344 个，腹外侧髓质中有 100 个。这些蛋白与真核起始翻译 (p = 3.09 × 10，z = 1.00)、真核延伸翻译 (p = 6.31 × 10，z = 6.01) 和凝血系统 (p = 1.32 × 10，z = 1.00) 的增加最显著相关。延髓中与改变的信号通路的关联最强，包括与之前分析的另外三个脑区 (额叶皮层、海马齿状回、角状突) 的比较。5HT2A 在 SUDC-FS 的延髓缝中的表达增加了 2.1 倍(p = 0.025)。病例史的加权基因相关网络分析 (WGCNA) 表明，FS 病史持续时间较长与延髓和腹外侧髓质中的蛋白水平显著相关；最显著的基因本体生物学过程是延髓中的细胞呼吸减少 (p = 9.8 × 10，corr = -0.80) 和腹外侧髓质中的突触小泡循环减少 (p = 1.60 × 10，corr = -0.90)。总体而言，FS 在 SUDC 中与延髓中的更多蛋白质差异相关，并与增加的翻译相关信号通路相关。未来的研究应评估这些变化是否是由 FS 引起的，或者是否以某种方式导致 FS 或 SUDC。
