Proteomic analysis on infantile spasm and prenatal stress
Jing Wang1, Juan Wang1, Ying Zhang1
1Department of Pediatrics, General Hospital of Chinese People's Liberation Army, Beijing, China.
Insights
Prenatal stress worsens infantile spasms (IS) in animal models. This study identifies key proteins, YWHAZ and CFL1, involved in the aggravated seizures and brain damage associated with IS under prenatal stress conditions.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Infantile spasms (IS) are a severe epileptic encephalopathy linked to cognitive dysfunction.
- Prenatal stress (PS) is a known risk factor for developing IS.
- The precise mechanisms underlying IS pathogenesis and the impact of PS remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms of brain damage in IS.
- To determine the specific effects of prenatal stress on IS development and severity.
- To identify key proteins involved in IS pathogenesis exacerbated by prenatal stress.
Main Methods:
- Established animal models for IS using N-methyl-d-aspartate (NMDA) and prenatal stress via cold-water swimming.
- Utilized a proteomics-based approach (gel electrophoresis, mass spectrometry) for differential protein expression analysis.
- Validated key protein findings using Western blot analysis and analyzed protein-protein interaction networks.
Main Results:
- Prenatal stress significantly increased spasm frequency and reduced latency in the IS model.
- Proteomics identified differentially expressed proteins in IS, including CFL1 and PKM2.
- Prenatal stress further altered protein expression, highlighting YWHAZ and CFL1 as potentially critical in aggravated IS.
Conclusions:
- The pathogenesis of IS involves disruptions in energy metabolism, brain development, and neural remodeling.
- Prenatal stress exacerbates seizure activity in IS models.
- YWHAZ and CFL1 are identified as key proteins potentially mediating the negative effects of prenatal stress on infantile spasms.
Abstract:
Infantile spasms (IS) are an age-dependent epileptic encephalopathy with severe cognitive dysfunction. Prenatal stress (PS) has been reported to increase the risk for IS through clinical and animal studies. We aim to investigate the mechanism of brain damage caused by IS and the effect of PS. Animals were divided into 4 groups: PS-spasm model, PS-saline control, NS-spasm model, and saline control. N-methyl-d-aspartate (NMDA) was used to induce spasm and swimming in cold water was used to induce PS. A proteomics-based approach was used to compare the NS-spasm model vs. saline control, and PS-spasm model vs. NS-spasm model. Gel image analysis was followed by mass spectrometric protein identification and bioinformatics analysis. We observed an increased spasm frequency (t=8.65, P<0.001), and a shorter latency period (t=3.96, P<0.001) in the PS-spasm model vs. the NS-spasm model. In the NS-spasm model vs. saline control, the main differentially expressed proteins were CFL1, PKM2, PRPS2, DLAT, CKB, DPYSL3, and SNAP25. In the PS-spasm model vs. NS-spasm model, MDH1 and YWHAZ were differentially expressed. YWHAZ was directly connected with CFL1 in protein networks. YWHAZ and CFL1 were further validated by Western blot analysis. The biological function of differentially expressed proteins indicates the pathogenesis of IS maybe relevant to energy metabolism, brain development, and neural remodeling. PS aggravated seizures in the NMDA-induced spasm model, YWHAZ, and CFL1 may be involved.
