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Updated: Sep 29, 2025
Lipidomics and Transcriptomics in Neurological Diseases
Published on: March 18, 2022
Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood
Dominique F Leitner1,2, Christopher William2,3, Arline Faustin2,3,4
1Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA.
Insights
Sudden unexplained death in childhood (SUDC) involves altered brain proteins, particularly in the frontal cortex and hippocampus. These proteomic changes may correlate with clinical factors, offering insights into SUDC pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Sudden unexplained death in childhood (SUDC) is a diagnosis of exclusion in children over one year of age.
- SUDC shares clinical and pathological similarities with sudden unexpected death in epilepsy (SUDEP), suggesting potential common mechanisms involving the hippocampus and cortex.
- Understanding the molecular underpinnings of SUDC is crucial for identifying potential causes and developing preventive strategies.
Purpose of the Study:
- To investigate molecular signaling pathways and protein expression differences in the brains of children who died from SUDC compared to controls.
- To identify specific brain regions and molecular pathways affected in SUDC.
- To explore correlations between proteomic findings and clinical history in SUDC cases.
Main Methods:
- Label-free quantitative mass spectrometry was employed on microdissected frontal cortex, hippocampus (dentate gyrus and CA1-3 regions).
- Proteomic data from 19 SUDC cases and 19 age- and sex-matched pediatric controls were analyzed.
- Pathway analysis and weighted gene correlation network analysis (WGCNA) were used to interpret differential protein expression and correlate findings with clinical data.
Main Results:
- Significant differential protein expression was observed in all analyzed brain regions: 660 proteins in the frontal cortex, 170 in the dentate gyrus, and 57 in the CA1-3 region.
- Key altered pathways included activated oxidative phosphorylation and inhibited EIF2 signaling in the frontal cortex, and activated acute phase response in the hippocampus.
- Post-mortem virology and clinical history (fever, febrile seizures) showed significant correlations with specific molecular changes in brain tissue.
Conclusions:
- Cortical and hippocampal proteomic alterations are present in SUDC cases.
- These protein changes correlate with specific clinical features, suggesting a link between molecular pathology and clinical presentation.
- Proteomic studies of SUDC cohorts are valuable for advancing the understanding of SUDC pathogenesis and may inform future preventive strategies.
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.
