Sex-specific Proteomic Analysis of Epileptic Brain Tissues: Insights from Human and Mouse Models
Abstract number :
3.479
Submission category :
2. Translational Research / 2C. Biomarkers
Year :
2024
Submission ID :
1534
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Zahra Sadri, MA – Southern Methodist University
Yibo Li, MS – Southern Methodist University
David Narvaiz, BS – Baylor University
Katherine Blandin, M.A. – Baylor University
Joaquin lugo, PhD – Baylor University
Amy Brewster, PhD – Southern Methodist University
Rationale: Epilepsy presents significant sex-based disparities in prevalence and manifestation. Epidemiological studies reveal that epilepsy is more prevalent in males, with lesional types being more common, whereas idiopathic generalized epilepsies are more frequently observed in females. These differences stress the importance of considering sex-specific factors in epilepsy diagnosis, treatment, and mechanistic research using preclinical models. To elucidate potential molecular differences that could explain these disparities and inform personalized treatment strategies, we conducted a proteomic analysis of epileptic brain tissues from both humans with drug-resistant epilepsy (DRE) and an experimental mouse model of genetic epilepsy.
Methods: We employed mass spectrometry-based proteomic analysis on brain tissues from DRE patients and the Pten knockout (KO) mouse model of genetic epilepsy with focal cortical dysplasia. Human samples included temporal cortex from 12 DRE adult patients (7 males, 5 females) and 5 non-epileptic (NE) controls (2 males, 3 females). Brain biopsies were collected with patients informed consent under approved IRB protocols (Indiana University Health Biorepository). Mouse samples included hippocampi from adult wild-type (WT) and Pten KO mice (4-5 per group and sex). Proteomic profiles were analyzed using principal component analysis (PCA) along with volcano plots to identify significant changes in protein expression.
Results: PCA revealed distinct clustering of brain proteomes between RE and NE cases, with 444 out of 3,610 proteins showing significant differences. In RE cases, males exhibited significant increases in 83 proteins compared to females, particularly in proteins associated with glial cells, immune function, ion channels, and synaptic processes. The mouse model showed similar sex-specific differences, with male and female Pten KO mice forming separate PCA clusters. Male Pten KO mice displayed significant upregulation in 127 proteins compared to females, notably in stress response, protein modification, cytoskeletal dynamics, and synaptic architecture-related proteins.
Conclusions: Our findings reveal more pronounced proteomic changes in the brains of male humans and mice with epilepsy compared to females. The results suggest that sex-specific pathways, particularly in neuroinflammatory responses and synaptic remodeling, are more prominent in males. These distinct proteomic signatures provide a foundation for developing targeted therapies that address the unique biological pathways active in the males and females’ brains with epilepsy, potentially leading to more effective and personalized treatment approaches.
Funding: NS096234; SMU Department of Biological Sciences
Translational Research