Biology subjects

Drago, D.

Publications and source records attributed to Drago, D..

4 recordsLinked to original sources

bioRxiv2025

Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models

Mutations in the GBA gene, which reduce {beta}-glucocerebrosidase (GCase) activity, represent the most significant genetic risk factor for Parkinsons disease (PD). Decreased GCase activity has also been observed in sporadic PD cases, supporting a broader role for GCase in the poorly understood mechanisms underlying PD etiopathogenesis. While most studies on the relationship between GBA mutations and PD have focused on neurons, evidence suggests that PD pathology promoted by GCase deficiency involves other cell types and, in particular, interactions between neuronal and glial cells. Here, we identify microglia as primary players undergoing significant alterations at early stages of the pathological processes triggered by a GCase impairment. Using both pharmacological and genetic mouse models of GCase deficiency, we observed microglial morphological, transcriptional and metabolic changes. Interestingly, these changes were associated with a cell-specific, significant reduction of microglial ATP levels. When microglial ATP depletion was reproduced in an in vitro system of co-cultured microglial and neuronal cells, the neuroprotective properties of microglia were compromised and neuronal susceptibility to oxidative stress was enhanced. These findings underscore the role of microglia in PD pathogenesis and point to a pathogenetic mechanism by which microglial metabolic disturbances leading to ATP depletion enhance neuronal vulnerability to injury and neurodegeneration. This mechanism could be targeted for therapeutic intervention aimed at mitigating PD risk and counteracting the development of PD pathology. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/656111v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@dfd3d7org.highwire.dtl.DTLVardef@ccf2c2org.highwire.dtl.DTLVardef@155d241org.highwire.dtl.DTLVardef@15ed00a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Inducible re-epithelialization of cancer cells increases autophagy and DNA damage: implications for breast cancer dormancy

Epithelial lineage differentiation is pivotal to mammary gland development and it can pause metastasis of breast cancer (BC) by inducing tumor dormancy. To simulate this, we expressed epithelial genes in mesenchymal BC cells. Inducible expression of the epithelial OVOL genes in metastatic BC cells suppressed proliferation and migration. We found that C1ORF116, an OVOLs target, is susceptible to genetic and epigenetic aberrations in BC. It is regulated by steroids and functions as a putative autophagy receptor that inhibits antioxidants like thioredoxin. Accordingly, boosting epithelialization lowered glutathione, elevated reactive oxygen species and increased both DNA oxidation and double strand breaks. Epithelialization also associated with redistribution of NRF2 and an altered interplay among p38, ATM, and the other kinases regulating the DNA damage response. Hence, hormonal regulation of OVOLs and chronic stress might permit epithelial differentiation and retard exit from dormancy, while altering redox homeostasis and permitting DNA damage accumulation, which may awaken dormant tumors.

cancer biology↗

bioRxiv2025

Avoidance of pyroptosis accounts for the relatively high metastatic potential observed in early hybrid EMT states

EMT converts epithelial (E) phenotypes to invasive mesenchymal (M) states. However, analyses of circulating tumor cells (CTCs) indicated that biphenotypic (E+M) CTCs better correlate with metastasis. Similarly, investigations of murine tumors undergoing EMT concluded that early E+M states posses the highest metastatic potential. To explore this, we selected in animals with breast cancer CTCs having progressively increasing intravasation abilities. This revealed that downregulation of arrestin Arrdc4 associates with CTC aggressiveness. In xenografts, depleting Arrdc4 accelerated tumor progression, whereas overexpression hindered progression in immunocompetent, but not in immunocompromised mice. Mechanistically, high Arrdc44 suppresses glucose uptake and enhances gasdermin E, triggering pyroptosis a type of pro-inflammatory cell death. Consistently, Arrdc4s lowest levels characterize the most metastatic biphenotypic states. In patients, both epigenetic and chromosomal aberrations downregulate ARRDC4 and predict poor prognosis. In summary, the uncovered mechanism portrays pyroptosis of biphenotypic EMT cells as a rheostat of CTCs, which may resolve the controversy on the role played by EMT in metastasis.

cancer biology↗

bioRxiv2024

MargheRita: an R package for LC-MS/MS SWATH metabolomics data analysis and confident metabolite identification based on a spectral library of reference standards

In the field of untargeted metabolomics, the deployment of high-resolution mass spectrometry technologies generates an immense volume of complex metabolite signals. This data density necessitates sophisticated computational frameworks for post-acquisition processing and the integration of specialized databases for accurate metabolite identification. Currently, many web-based data processing solutions offer fragmented workflows, covering only specific stages of the analysis and frequently requiring researchers to migrate data across multiple, often incompatible, platforms. To address these challenges, we introduced margheRita, an R package designed to streamline the workflow for untargeted metabolomic profiling. Developed to work seamlessly with MS-DIAL output, margheRita provides a comprehensive pipeline for liquid chromatography-tandem mass spectrometry (LC-MS/MS) data. This tool is particularly effective for Data-Independent Acquisition (DIA) experiments, where the high-resolution acquisition of all MS/MS spectra demands rigorous and integrated processing capabilities. A key innovation of margheRita is its ability to significantly enhance fragment matching accuracy. It achieves this by utilizing an original, curated high-quality spectral library from authentic reference standards. This library includes data acquired in both positive and negative ionization polarities using various chromatographic columns, ensuring high versatility. By bridging the gap between initial MS-DIAL processing and final biological insights, margheRita offers a holistic solution from metabolite identification to the functional interpretation of complex biological datasets.

bioinformatics↗