Raphe and Ventrolateral Medulla Proteomics in Sudden Unexplained Death in Childhood with Febrile Seizure History

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, 28.8% 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 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=3.09x10-7, z=1.00), eukaryotic translation elongation (p=6.31x10-49, z=6.01), and coagulation system (p=1.32x10-5, z=1.00), respectively. 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). Histological analyses 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=9.8x10-5, corr=-0.80) in medullary raphe and synaptic vesicle cycle (p=1.60x10-7, corr=-0.90) in the ventrolateral medulla. Overall, FS in SUDC was associated with more protein differences in the medullary raphe and was related to increased translation-related signaling pathways. Our study informs on SUDC pathogenesis and the potential development of prognostic biomarkers and preventive therapeutic strategies.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Beatrix Ueberheide  

PROVIDER: MSV000095576 | MassIVE | Mon Aug 12 11:51:00 BST 2024

REPOSITORIES: MassIVE