Biology subjects

Skoulakis, E. M. C.

Publications and source records attributed to Skoulakis, E. M. C..

4 recordsLinked to original sources

bioRxiv2025

RpS12-mediated induction of the Xrp1short isoform links ribosomal protein mutations to cell competition

Cell competition, a universal yet enigmatic phenomenon, eliminates less-fit cells via interactions with their neighbors. It was originally described in Drosophila mosaics, where heterozygous ribosomal protein (Rp+/-) mutant cells are eliminated by wild-type neighbors. The transcription factor Xrp1 mediates most of the Rp+/- -associated phenotypes, including reduced competitiveness and translation. Although RpS12 is required for Xrp1 induction in Rp+/- cells, the mechanism remained unresolved. We demonstrate that RpS12, via alternative splicing, induces the Xrp1 short (Xrp1short) isoform expression in Rp+/- cells, which is both necessary and sufficient for their elimination. Strikingly, RpS12 overexpression in wild-type cells is sufficient to induce Xrp1short expression and confer a "loser" phenotype. While Xrp1long isoform is not required in Rp+/- cells, expression of either Xrp1 isoform is sufficient to promote the loser status in wild-type cells. We further identify Syncrip, an RNA-binding protein reduced in Rp+/- cells, as a critical Xrp1 suppressor; its depletion in wild-type cells activates Xrp1-dependent competition. Our findings establish RpS12s specialized function in Xrp1short promotion, not proteotoxic stress, as the primary driver in Rp+/- cells, providing new perspectives that challenge and refine prevailing models. Our work contributes in long-standing questions about ribosomal protein-linked fitness surveillance and provides insights into ribosomopathy pathologies.

developmental biology↗

bioRxiv2024

Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity in Drosophila

BackgroundDisease-modifying therapies for tauopathies like Alzheimers disease have targeted Tau hyperphosphorylation and aggregation, as both pathological manifestations are implicated in Tau-mediated toxicity. However, the relative contributions of these pathology-linked changes to Tau neurotoxicity remain unclear. MethodsLeveraging the genetic tractability of Drosophila, we generated multiple inducible human Tau transgenes with altered phosphorylation status and/or aggregation propensity. Their individual and combined impact was tested in vivo by quantifying Tau accumulation and neurodegenerative phenotypes in the aging fly nervous system. ResultsWe report that phospho-mimicking Tau (hTau2N4RE14) induced profound neurodegeneration, supporting a neurotoxic role for phosphorylation. However, when we rendered hTau2N4RE14 aggregation incompetent, by deleting the 306VQIVYK311 motif in the microtubule-binding region, neurotoxicity was abolished. Moreover, a peptide inhibitor targeting this motif efficaciously reduced Tau toxicity in aging Drosophila. ConclusionNeurodegeneration mediated by Tau hyperphosphorylation is gated via at least one aggregation-mediating motif on the protein. This highlights the primacy of blocking Tau aggregation in therapy, perhaps without the need to clear phosphorylated species.

neuroscience↗

bioRxiv2021

Evidence for Free Radical Drug Ligands in class A G-protein Coupled Receptors

We analyse the conformation of 22 cationic ligands bound to G-protein coupled receptors of known structure and find three ligands that are present inside receptors not in their closed shell cation form, but as neutral radicals, i.e. after addition of an electron to the ligand. The implications of this finding for GPCR function are discussed and a possible experimental test is proposed.

pharmacology and toxicology↗

bioRxiv2021

Bee foraging preferences, microbiota and pathogens revealed by direct shotgun metagenomics of honey

Honeybees (Apis mellifera) continue to succumb to human and environmental pressures despite their crucial role in providing essential ecosystem services. Owing to their foraging and honey production activities, honeybees form complex relationships with species across all domains, such as plants, viruses, bacteria (symbiotic and pathogenic), and other hive pests, making honey a valuable biomonitoring tool for assessing their ecological niche. Thus, the application of honey shotgun metagenomics (SM) has paved the way for a detailed description of the species honeybees interact with, in order to better assess the multiple factors governing their health. Here, we describe the implementation of optimized honey DNA extraction methodology coupled to direct shotgun metagenomics (Direct-SM) analysis, and to a computationally optimised and validated pipeline for taxonomic classification of species detected in honey. By comparing honey collected across 3 harvesting seasons in a stable apiary, we show that Direct-SM can describe the variability of sampled plant species, revealing honeybee behavioural adaptation. In addition, we reveal that Direct-SM can non-invasively capture the diversity of species comprising the core and non-core bacterial communities of the gut microbiome. Finally, we show that this methodology is applicable for the monitoring of pathogens and particularly for the biomonitoring varroa infestation. These results suggest that Direct-SM can accurately and comprehensively describe honeybee ecological niches and can be deployed to assess bee health in the field.

ecology↗