4.6 Article

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

期刊

ACTA NEUROPATHOLOGICA
卷 143, 期 5, 页码 585-599

出版社

SPRINGER
DOI: 10.1007/s00401-022-02414-7

关键词

SUDC; Febrile seizures; Proteomics; Laser capture microdissection

资金

  1. Sudden Unexplained Death in Childhood (SUDC) Foundation
  2. Moss Pieratt Foundation
  3. Finding A Cure for Epilepsy and Seizures (FACES)
  4. National Institutes of Health [AG066512, AG060882]

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This study used mass spectrometry to analyze the differential protein expression in frontal cortex and hippocampus of sudden unexplained death in childhood (SUDC) cases. The results showed activated oxidative phosphorylation and inhibited EIF2 signaling in the frontal cortex, and activated acute phase response in the hippocampus, suggesting potential mechanisms for SUDC. The weighted gene correlation network analysis of clinical history also revealed modules associated with viral pathology, fever, and febrile seizure history.
Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 x 10(-15), z = 4.08) and inhibited EIF2 signaling (p = 2.0 x 10(-21), z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 x 10(-6), z = 2.65) and CA1-3 (p = 4.7 x 10(-6), z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 x 10(-5)) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 x 10(-3)) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 x 10(-5)) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 x 10(-3)). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.

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