Thesis: Irene Soler Saez

Directors: Marta R. Hidalgo García, María de la Iglesia Vayá y Francisco García García

Abstract: Dysfunction of the central nervous system (CNS) gives rise to a wide range of neurological disorders. This work contributes to the understanding of CNS diseases through three different studies: identifying sex-differential alterations in multiple sclerosis (MS) analyzing (1) single-cell transcriptomics and (2) metagenomics data, and (3) examining how the characterization of MS, together with other neurodegenerative diseases, provides insights into the neurobiology of brain tumors. MS is a chronic autoimmune and neurodegenerative condition that progresses from acute, inflammation-driven episodes to progressive stages dominated by neurodegeneration. Females exhibit a higher risk of developing MS and show more pronounced inflammatory activity, while males are more susceptible to rapid and severe neurodegeneration. Our single-cell transcriptomic analyses identified candidate genes, functional processes, and pathways in CNS cell types that may contribute to these sex-differential clinical outcomes. In the inflammation-predominant form of MS, female immune cells showed increased expression of inflammation-related genes. Meanwhile, males exhibited increased expression of genes linked to mitochondrial impairment. Larger differences were reported in CD8+ T cells from the primary progressive form, with females presenting increased expression of genes that may favor homeostasis and males exhibiting cytolytic profiles. Our next study revealed consistent sex-associated microbial taxa through the meta-analysis of metagenomic datasets from the human gut (e.g., Eggerthella, Eisenbergiella, and Flavonifractor more abundant in MS females; Prevotella in MS males). Some of these genera were associated with disease progression. Finally, we explored whether melanoma brain metastases share molecular mechanisms with MS, Alzheimer’s disease, and Parkinson’s disease. We identified more than 200 common dysregulated genes, some of which are involved in key biological processes that suggest shared alterations between neurodegeneration and tumor progression. All analyses were performed in silico using publicly available datasets, and results are accessible through interactive web tools.