Biology subjects

Berdasco, C.

Publications and source records attributed to Berdasco, C..

3 recordsLinked to original sources

bioRxiv2026

Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism

Cancer cachexia causes pathological weight loss, anorexia, and depressive symptoms, culminating in increased mortality. Using mouse models of pancreatic cancer cachexia, we identify tumor and hepatic inflammatory signaling, multi-organ energy charge depletion, and altered tryptophan metabolism. Metabolomic profiling and stable isotope tracing revealed altered tryptophan fates: serotonin depletion and kynurenine accumulation across tumor, liver, muscle and spleen. Kynurenine accumulation involved accelerated conversion of tryptophan to kynurenine with slowed downstream conversion to kynurenic acid. Restoring serotonin activity pharmacologically or metabolically normalized feeding, locomotion, and depression-like behavior, but wasting, tumor burden, and survival remained unchanged. Blocking kynurenine production or kynurenine-mediated AhR activation pharmacologically produced similar results. Thus, in cancer cachexia, the tryptophan pathway is subverted to deplete serotonin and accumulate kynurenine. This subversion contributes to cachexia-associated behavioral and feeding defects but not lethal systemic catabolism.

cancer biology↗

bioRxiv2026

Wasf1 deletion attenuates tau hyperphosphorylation, microglial state transition, and cognitive deficits in P301S tau mice

We previously reported that WAVE1, a major activator of Arp2/3 complex-mediated actin polymerization, is downregulated in postmortem brains of Alzheimers disease (AD) and that WAVE1 regulates amyloid precursor protein trafficking and amyloid-{beta} production. However, its role in tau pathology remains unknown. Here, we demonstrate that WAVE1 activity is suppressed in P301S tau mice through elevated inhibitory phosphorylation. Strikingly, WAVE1 gene (Wasf1) knockout in P301S tau mice significantly reduces tau hyperphosphorylation and improves cognition, suggesting a compensatory role for WAVE1 suppression in tau pathogenesis. Single-nucleus RNA sequencing reveals that Wasf1 deletion in P301S tau mice reverses microglial state transitions, with minimal impact on other brain cell types. Wasf1 mRNA is highly translated in microglia in non-Tg mice, while its expression is downregulated in P301S tau mice. Wasf1 knockdown in BV2 microglia cells enhances the degradation of engulfed tau fibrils, indicating WAVE1 as an endogenous regulator of microglial function. Additionally, CellChat analysis indicates that Wasf1 deletion alters microglial autocrine signaling and their interactions with other cell types in P301S tau mice. These findings, taken together, suggest that Wasf1 deletion restores homeostatic microglial function, mitigates tau pathology, and alleviates cognitive deficits, highlighting WAVE1 as a potential therapeutic target for tauopathy-related dementias.

neuroscience↗

bioRxiv2020

Cognitive deficits found in a pro-inflammatory state are independent of ERK 1/2 signaling in the murine brain hippocampus treated with Shiga toxin 2 from enterohemorrhagic Escherichia Coli

Shiga toxin 2 (Stx2) from enterohemorrhagic Escherichia coli (EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS) and acute encephalopathy. The mortality rate in HUS increases significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. Results demonstrate that systemic administration of a sublethal dose of Stx2 reduced memory index and produced depression like behavior, pro-inflammatory cytokine release and NF-kB activation independent of the ERK 1/2 signaling pathway. On the other hand, LPS activated NF-kB dependent on ERK 1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.

pathology↗