Biology subjects

Galan-Ganga, M.

Publications and source records attributed to Galan-Ganga, M..

3 recordsLinked to original sources

bioRxiv2025

Sex-dependent interferon signaling drives female-biased vulnerability in Alzheimer's disease

Alzheimers disease (AD) disproportionately affects women, yet the neurobiological mechanisms underlying this sex bias remain poorly understood. Here, we identify a sex-dependent activation of type I interferon (IFN-I) signaling as a contributor to this disparity. Transcriptomic profiling of brain from AD patients revealed selective enrichment of IFN-I pathway in females. This immune signature was mirrored in the APP/PS1 mouse model of AD, where females exhibited more pronounced amyloid accumulation, neuroinflammation, and neurodegeneration. Acute IFN-I activation reproduced pathological features of AD, whereas chronic IFN-I elevation in APP/PS1 mice aggravated disease progression. In contrast, pharmacological targeting of IFN-I response by inhibiting the cGAS-STING pathway in APP/PS1 female mice reduced neuropathological burden, and preserved cognitive performance. Together, these findings identify interferon signaling as a modifiable and sex-linked driver of AD pathology. Our study uncovers a critical neuroimmune mechanism contributing to female-biased vulnerability and highlights interferon modulation as a promising therapeutic strategy in AD.

neuroscience↗

bioRxiv2024

A double hit affecting the IKZF1-IKZF2 tandem in immune cells of schizophrenic patients regulate specific symptoms

Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenic-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from human patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenic-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.

neuroscience↗

bioRxiv2020

MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

cancer biology↗