Biology subjects

Selloum, M.

Publications and source records attributed to Selloum, M..

7 recordsLinked to original sources

bioRxiv2026

Obesity-related alterations in plasma metabolomics and fecal microbiota in Down syndrome Dp(16)1Yey mice

Background/ObjectivesIndividuals with Down syndrome (DS) are at increased risk of obesity and metabolic comorbidities, yet the mechanisms underlying these conditions remain unclear. Here we investigated how DS-associated genetic condition interacts with diet and metabolic pathways in the Dp(16)1Yey mouse model of DS. MethodsUntargeted plasma metabolomics was performed in Dp(16)1Yey and control mice, subjected to either control or high-fat diet (HFD). Raw data were processed, and features were annotated. Statistical analyses were conducted in R, and pathway analysis was performed with MetaboAnalyst v5.0. Fecal microbiome was obtained using 16SrRNAseq and analyzed using phyloseq in R. ResultsDiet exerted the strongest effect on mice plasma metabolome, followed by sex and genotype. Seventy-five diet-responsive metabolites were enriched in amino acid and nucleotide metabolism. Genotype-driven changes affected 34 metabolites, notably impacting amino acid and taurine-hypotaurine metabolism. Fifty-six sex-associated metabolites highlighted disruptions in aromatic amino acid biosynthesis and pyrimidine metabolism. A significant Diet*Genotype interaction was observed for five metabolites, including a marked reduction in the microbiota-derived metabolite 3-indolepropionic acid (IPA) in Dp(16)1Yey mice on HFD. Both genotype and diet exerted pronounced effects on fecal microbiome with selective depletion of the IPA-producing Clostridia in Dp1Yey mice under HFD. ConclusionSegmental trisomy in Dp(16)1Yey mice modulates the host metabolic response to dietary fat, partly through microbiota-derived metabolites such as IPA. These findings highlight the importance of genotype, diet, and microbiome interactions in shaping metabolic disease risk in DS and point toward microbiota-targeted dietary interventions.

neuroscience↗

bioRxiv2026

Cardiorenal and hepatic dysfunctions underlie metabolic alterations in the spinocerebellar ataxia type 7 mice

Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine expansion disorder characterized by progressive cerebellar and retinal degeneration leading to ataxia and blindness. While mutant ATXN7 is ubiquitously expressed, most studies have focused on neurological symptoms, and peripheral contributions to pathology remain poorly understood. Here, we investigated systemic abnormalities in SCA7140Q/5Q knock-in mice, a model of early-onset disease. Using longitudinal metabolic profiling, ultrasound imaging, and histopathology, we identified early and progressive dysfunction of the kidney, liver, and heart. Renal impairment was marked by uremia, polyuria with abnormal calcium and glucose excretion, tubular epithelial cell loss, and podocyte dedifferentiation, including the reappearance of primary cilia and pedicel effacement. Hepatic alterations included dysregulated lipid metabolism, elevated bilirubin, and reduced iron levels, contributing to anemia. Cardiac dysfunction manifested as reduced stroke volume as early as 11 weeks, suggesting a cardiorenal syndrome. Together, these organ-specific changes resulted in systemic metabolic disturbances such as dyslipidemia, iron deficiency anemia, thrombocytosis, and chronic inflammation, detectable before the onset of motor incoordination. Our findings demonstrate that peripheral organ dysfunction is an early and integral feature of SCA7 pathogenesis, with renal and cardiac impairments emerging prior to neurological decline. These results highlight the value of systemic biomarkers for disease monitoring and suggest that targeting peripheral pathology may provide therapeutic benefit. More broadly, they underscore the need to view SCA7 not solely as a neurodegenerative disorder but as a multi-organ disease.

pathology↗

bioRxiv2025

Establishing Comprehensive Transthoracic Echocardiography Reference Ranges for Mouse Models: Insights into the Impact of Anesthesia, Sex, and Age

Mouse models play a critical role in cardiology research, offering valuable insights into the molecular mechanisms, genetics, and potential treatments for cardiovascular diseases. However, the ability to transfer findings in mice between studies is limited by the absence of standardized protocols and valid reference values for the assessment of normal cardiac function in mice. This study aims to establish comprehensive transthoracic echocardiography (TTE) reference ranges for mice, particularly focusing on C57BL/6N wildtype controls. The study, which includes data from over 15,000 mice through the International Mouse Phenotyping Consortium (IMPC), highlights how variables such as sex, age, body weight, and anesthesia affect TTE parameters. The findings showed that anesthesia is the primary predictor of variability in cardiac function. Isoflurane and tribromoethanol anesthetized mice presented with modified cardiac function compared to conscious mice. Additionally, we observed minimal sex differences in cardiac morphology and function, except for small variations influenced by anesthesia. The effects of aging on cardiac function were modest, characterized by a decrease in heart rate and subtle changes in ventricular dimensions without evidence of pathological remodeling, likely attributable to disease-free cardiovascular aging. Validation of the reference ranges across multiple mouse strains showed that these values provide a reliable baseline for experiments involving cardiac function in mice. The data underscore the importance of using anesthesia-specific reference values when interpreting TTE results, ensuring robust comparisons in genetic and pharmacological studies. These reference ranges serve as quality assurance tools for future cardiac studies in mice, offering insights into typical TTE parameter values, supporting the detection of experimental perturbations, and contributing to more effective translation of findings from mouse to human.

genetics↗

bioRxiv2025

Astroglial deficiency for oligophrenin-1 contributes to intellectual disability

Neurodevelopmental disorders, including X-linked intellectual disability, autism spectrum disorder or schizophrenia, can result from the mutation of oligophrenin-1 (Ophn1), encoding a Rho-GTPase-activating protein. Ophn1 regulates synaptic development and function, in part via cytoskeleton reorganization, and is expressed in both neurons and astrocytes. Despite the crucial role of astrocytes in synapse function, altered in neurodevelopmental disorders, and their Ophn1 expression, the specific impact of astroglial Ophn1 deficiency on synaptic transmission and behavior remains unknown. Here, we show that Ophn1 deficiency postnatally in hippocampal astrocytes impairs synaptic transmission, short-term plasticity and spatial working memory in adults. This involves an adenosine A1 receptor-dependent presynaptic mechanism associated with astroglial morphological rearrangements resulting in increased astroglial synapse coverage. The structural, functional and behavioral alterations induced by astroglial Ophn1 deficiency are rescued in adults by pharmacological inhibition of the RhoA/ROCK pathway. Our findings uncover an important role for astroglial Ophn1 deficiency in synaptic and behavioral dysfunctions, pointing to a novel cellular therapeutic target for neurodevelopmental disorders.

neuroscience↗

bioRxiv2022

Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in brain phenotypes and unveils a new role for the major vault protein

Using mouse genetic studies, we set out to identify which of the 30 genes causes brain size and other NeuroAnatomical Phenotypes (NAPs) at the autism-associated 16p11.2 locus. We show that multiple genes mapping to this region interact to regulate brain size in contrast to previous studies, with female significantly less affected. Major Vault Protein (MVP), the main component of the vault organelle, is a highly conserved protein found in higher and lower eukaryotic cells, yet its function is not understood. Here we find MVP expression highly specific to the limbic system and Mvp as the top driver gene of NAPs, regulating the morphology of neurons, postnatally and specifically in male. Finally, we demonstrate that the double hemideletion Mvp::Mapk3 rescues NAPs, increases phosphorylation of ERK and alters behavioral performances, suggesting that MVP and ERK share the same signalling pathway, in vivo. Our results highlight that sex-specific cellular and neuroanatomical mechanisms must be considered in neurological disorders such as autism. Most importantly, it provides the first evidence for the involvement of the vault organelle in the regulation of the mammalian brain size and limbic structures.

genetics↗

bioRxiv2021

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Mutation in the DYRK1A gene located on human chromosome 21 (Hsa21) leads to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles (MRD7). Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach. Author summaryThe Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A, DYRK1A, drives cognitive alterations with increased dose in Down syndrome (DS) or with reduced dose in mental retardation disease 7 (MRD7). Here we report that specific and complete loss of Dyrk1a in glutamatergic neurons induced a range of specific cognitive phenotypes and alter the expression of genes involved in neurotransmission in the hippocampus. We further explored the consequences of Dyrk1a dosage in glutamatergic neurons on the cognitive phenotypes observed respectively in MRD7 and DS mouse models and we found specific roles in long-term explicit memory with no impact on motor activity, short-term working memory, and susceptibility to epilepsy. Then we demonstrated that DYRK1A is a component of the glutamatergic post-synapse and interacts with several component such as NR2B and PSD95. Altogether our work describes a new role of DYRK1A at the glutamatergic synapse that must be considered to understand the consequence of treatment targeting DYRK1A in disease.

neuroscience↗

bioRxiv2019

Soft Windowing Application to Improve Analysis of High-throughput Phenotyping Data

MotivationHigh-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximises analytic power while minimising noise from unspecified environmental factors.\n\nResultsHere we introduce \"soft windowing\", a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant p-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft windowed and non-windowed approaches, respectively, from a set of 2,082 mutant mouse lines. Our method is generalisable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources.\n\nAvailability and ImplementationThe method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin.

bioinformatics↗