Dominique F. Leitner, Christopher William, Arline Faustin, Evgeny Kanshin, Matija Snuderl, Declan McGuone, Thomas Wisniewski, Beatrix Ueberheide, Laura Gould, Orrin Devinsky
{"title":"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","authors":"Dominique F. Leitner, Christopher William, Arline Faustin, Evgeny Kanshin, Matija Snuderl, Declan McGuone, Thomas Wisniewski, Beatrix Ueberheide, Laura Gould, Orrin Devinsky","doi":"10.1007/s00401-024-02832-9","DOIUrl":null,"url":null,"abstract":"<div><p>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 <i>p</i> < 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 (<i>p</i> = 3.09 × 10<sup>–7</sup>, z = 1.00), eukaryotic translation elongation (<i>p</i> = 6.31 × 10<sup>–49</sup>, z = 6.01), and coagulation system (<i>p</i> = 1.32 × 10<sup>–5</sup>, 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 (<i>p</i> = 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 (<i>p</i> = 9.8 × 10<sup>–5</sup>, corr = − 0.80) in medullary raphe and decreased synaptic vesicle cycle (<i>p</i> = 1.60 × 10<sup>–7</sup>, 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.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3000,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02832-9.pdf","citationCount":"0","resultStr":"{\"title\":\"Raphe and ventrolateral medulla proteomics in sudden unexplained death in childhood with febrile seizure history\",\"authors\":\"Dominique F. Leitner, Christopher William, Arline Faustin, Evgeny Kanshin, Matija Snuderl, Declan McGuone, Thomas Wisniewski, Beatrix Ueberheide, Laura Gould, Orrin Devinsky\",\"doi\":\"10.1007/s00401-024-02832-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <i>p</i> < 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 (<i>p</i> = 3.09 × 10<sup>–7</sup>, z = 1.00), eukaryotic translation elongation (<i>p</i> = 6.31 × 10<sup>–49</sup>, z = 6.01), and coagulation system (<i>p</i> = 1.32 × 10<sup>–5</sup>, 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 (<i>p</i> = 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 (<i>p</i> = 9.8 × 10<sup>–5</sup>, corr = − 0.80) in medullary raphe and decreased synaptic vesicle cycle (<i>p</i> = 1.60 × 10<sup>–7</sup>, 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. 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Raphe and ventrolateral medulla proteomics in sudden unexplained death in childhood with febrile seizure history
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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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.
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