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

ABSTRACT: 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 × 10^-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10^-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10^-6, z = 2.65) and CA1-3 (p = 4.7 × 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 × 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 × 10^-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10^-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 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.

SUBMITTER: Leitner DF

PROVIDER: S-EPMC8953962 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Leitner Dominique F DF William Christopher C Faustin Arline A Askenazi Manor M Kanshin Evgeny E Snuderl Matija M McGuone Declan D Wisniewski Thomas T Ueberheide Beatrix B Gould Laura L Devinsky Orrin O

Acta neuropathologica 20220325 5

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 la ...[more]

PMID: 35333953

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Project description:Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioural disorders, and increased mortality from direct (e.g. sudden unexpected death in epilepsy, accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signalling networks associated with seizures in epilepsy with a broad range of aetiologies, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry was performed on the hippocampal cornu ammonis 1-3 region (CA1-3), frontal cortex and dentate gyrus microdissected from epilepsy and control cases (n = 14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1 - 3 region, 296 proteins in the frontal cortex and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signalling and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein subunit beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signalling and G-protein-coupled receptors in epilepsy. Our results provide insights into common molecular mechanisms underlying epilepsy across various aetiologies, which may allow for novel targeted therapeutic strategies.

Project description: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.

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

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

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