Biology subjects

Moreau, D.

Publications and source records attributed to Moreau, D..

11 recordsLinked to original sources

bioRxiv2025

Lysosome-Dependent Sphingolipid Regulation as a potential therapeutic Target for Cohen Syndrome

Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by biallelic mutations in the VPS13B gene, affecting approximately 50,000 individuals worldwide. Clinical features include postnatal microcephaly, developmental delay, intellectual disability, neutropenia, and retinal dystrophy. VPS13B belongs to the bridge-like lipid transfer protein (BLTP) family, which also includes VPS13A, VPS13C, and VPS13D in mammals. Although its precise function remains unclear, VPS13B localizes to the Golgi complex, and its loss leads to Golgi fragmentation, a consistent cellular phenotype observed in VPS13B-deficient models. We used the rescue of this cell-autonomous phenotype as the basis for a microscopy-based high-throughput screening assay, through which we identified several small molecules capable of restoring Golgi morphology. Most of these compounds shared a common mechanism of action, relying on lipid accumulation in acidic organelles due to their cationic amphiphilic properties (CADs). Lipidomic profiling revealed a reduction in C18-N-acyl sphingolipids as a characteristic feature of VPS13B knockout (KO) cells, a defect that was reversed by the majority of the identified compounds. To evaluate the physiological relevance of these findings, we tested two compounds, azelastine and raloxifene, in cortical organoids (COs) derived from VPS13B KO human pluripotent stem cells. These organoids exhibited smaller size and reduced neurite outgrowth, reminiscent of the secondary microcephaly observed in CS patients. Treatment with either compound significantly recovered the neurite outgrowth phenotype, reinforcing physiological relevance of the compound effect. Taken together, our findings highlight a potential effect of the CAD on lysosome-dependent sphingolipid regulation, allowing the recovery of Golgi integrity and partial rescue in the cortical organoid CS model. Although additional studies are required to delineate the exact molecular targets, this work uncovers a potential mechanism that could be leveraged for the treatment of CS.

cell biology↗

bioRxiv2024

Inkjet-printed transparent electrodes for electrical brain stimulation

Electrical stimulation is a powerful tool for investigating and modulating brain activity, as well as for treating neurological disorders. However, understanding the precise effects of electrical stimulation on neural activity has been hindered by limitations in recording neuronal responses near the stimulating electrode, such as stimulation artifacts in electrophysiology or obstruction of the field of view in imaging. In this study, we introduce a novel stimulation device fabricated from conductive polymers that is transparent and therefore compatible with optical imaging techniques. The device is manufactured using a combination of microfabrication and inkjet printing techniques and is flexible, allowing better adherence to the brains natural curvature. We characterized the electrical and optical properties of the electrode and evaluated its performance in the brain of an anesthetized mouse. Furthermore, we combined experimental data with a finite-element model of the in-vivo experimental setup to estimate the maximum electric field that the highly transparent device can generate in the mouse brain. Our findings indicate that the device can generate an electric field as high as 300 V/m, demonstrating its potential for studying and manipulating neural activity using a range of electrical stimulation techniques relevant to human applications. Overall, this work presents a promising approach for developing versatile new tools to apply and study electrical brain stimulation.

bioengineering↗

bioRxiv2024

Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbene scaffolds by a fungal secretome

This study evaluated the efficacy of a high-throughput Dictyostelium discoideum - Mycobacterium marinum Dd-Mm infection system by first benchmarking it against a set of antibiotics and second in screening a library of natural product (NP) derivatives for anti-infective activity against intracellular Mycobacterium marinum (Mm). The study observed no activity of pyrazinamide against Mm, consistent with known resistance patterns, and confirmed other antibiotics, such as rifampicin and bedaquiline, with activity below defined antibacterial susceptibility breakpoints. From screening a small library of NP derivatives, trans-{delta}-viniferins emerged as promising anti-infective scaffolds, particularly two compounds which exhibited an anti-infective activity on Mm during infection but not on Mm in broth, 17 with an IC50 of 18.1 {micro}M, and 19 with an IC50 of 9 {micro}M). Subsequent exploration via halogenation and structure-activity relationship (SAR) studies led to the identification of derivatives with improved selectivity and potency. The observed anti-infective phenotype may involve mechanisms such as blocking mycobacterial virulence factors or boosting host defense. Furthermore, the study highlights the potential of natural product-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds. IMPORTANCEThis study underscores the significance of leveraging natural product-inspired approaches and innovative infection models in search for novel anti-infective compounds. By benchmarking and employing high-throughput Dictyostelium discoideum-Mycobacterium marinum infection system on a small, focused library of natural product derivatives, the study identified trans-{delta}-viniferins as promising anti-infective scaffolds against Mycobacterium marinum, opening potential therapeutic avenues for combating tuberculosis. The findings highlight the value of exploring nature-inspired chemistry for drug discovery and addressing global health challenges.

microbiology↗

bioRxiv2023

Reassessing the functional significance of BOLD variability

BOLD variability (SDBOLD) has emerged as a unique measure of the adaptive properties of neural systems that facilitate fast, stable responding, based on claims that SDBOLD is independent of mean BOLD signal (meanBOLD) and a powerful predictor of behavioural performance. We challenge these two claims. First, the apparent independence of SDBOLD and meanBOLD may reflect the presence of deactivations; we hypothesize that while SDBOLD may not be related to raw meanBOLD it will be linearly related to absolute meanBOLD. Second, the observed relationship between SDBOLD and performance may be an artifact of using fixed-length trials longer than response times. Such designs provide opportunities to toggle between on- and off-task states, and fast responders likely engage in more frequent state-switching, thereby artificially elevating SDBOLD. We hypothesize that SDBOLD will be higher and more strongly related to performance when using such fixed-length trials relative to self-paced trials that terminate upon a response. We test these two hypotheses in an fMRI study using blocks of fixed-length or self-paced trials. Results confirmed both hypotheses: (1) SDBOLD was robustly related with absolute meanBOLD; and (2) toggling between on- and off-task states during fixed-length trials reliably contributed to SDBOLD. Together, these findings suggest that a reappraisal of the functional significance of SDBOLD as a unique marker of cognitive performance is warranted.

neuroscience↗

bioRxiv2019

Investigating the Influence of the Brain-Derived Neurotrophic Factor Val66Met Single Nucleotide Polymorphism on Familiarity and Recollection Event-Related Potentials

The Val66Met single nucleotide polymorphism (SNP) has previously been reported to impact performance on recognition memory tasks. Whether the two subprocesses of recognition--familiarity and recollection--are differentially impacted by the Val66Met SNP remains unknown. Using event-related potentials (ERPs) recorded during a source memory task, we attempted to dissociate these two subprocesses. Behaviourally, we used participants scores on an item-recognition subtask as a measure of familiarity, and participants scores on a source-recognition subtask as a measure of recollection. Our findings reveal that Val/Val individuals outperform Met allele carriers on the item-but not the source-recognition task. Electrophysiologically, we were interested in the N400, an early frontal component previously linked to familiarity, and the late positive complex (LPC), a posterior component linked to recollection. We found evidence for Val/Val individuals having larger amplitudes of the LPC compared to Met allele carriers, and evidence for no difference in the N400 amplitudes of these groups. Based on the lack of dissociation between familiarity- and recollection-specific ERPs at the LPC time window, we argue that our behavioural and ERP results might reflect better item-recognition for Val/Val individuals compared to Met allele carriers. We further suggest that both these results reflect differences related to familiarity, rather than recollection.

neuroscience↗

bioRxiv2018

The Brain-Derived Neurotrophic Factor Val66Met Genotype Does Not Influence the Grey or White Matter Structures Underlying Recognition Memory

A single nucleotide polymorphism (SNP) in the gene coding for brain-derived neurotrophic factor (BDNF) has previously been associated with a reduction in recognition memory performance. While previous findings have highlighted that this SNP contributes to recognition memory, little is known about its influence on subprocesses of recognition, familiarity and recollection. Previous research has reported reduced hippocampal volume and decreased fractional anisotropy in carriers of the Met allele across a range of white matter tracts, including those networks that may support recognition memory. Here, we used a source memory task to measure accuracy on each recognition subprocess, in order to determine whether the Val66Met SNP influences these equally. Additionally, we compared grey matter volume between these groups for structures that underpin familiarity and recollection separately. Finally, we used probabilistic tractography to reconstruct tracts that subserve each of these two recognition systems. Behaviourally, we found group differences on the familiarity measure, but not on recollection. However, we did not find any group difference on grey- or white-matter structures. Together, these results suggest a functional influence of the Val66Met SNP that is independent of coarse structural changes, and nuance previous research highlighting the relationship between BDNF, brain structure, and behaviour.

neuroscience↗

bioRxiv2018

Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice

Most cells acquire cholesterol by endocytosis of circulating LDLs. After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver of Npc1-/- mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.

cell biology↗

bioRxiv2018

Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells

In specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in non-specialized cells, and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel MCOLN1, as well as FYCO1, the AP1 adaptor and its partner Gadkin. We conclude that endolysosomes in non-specialized cells can acquire secretory functions elicited by cyclodextrin, and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.

cell biology↗

bioRxiv2018

Human sensory Long-Term Potentiation (LTP) predicts visual memory performance and is modulated by the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism

BackgroundLong-Term Potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory, and to gain additional insight into variations in memory function and memory decline. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to BDNF Val66Met; a single nucleotide polymorphism implicated in memory function.\n\nMethods28 participants (15 female) were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP-like enhancements of the visually-evoked response, and a test of visual memory.\n\nResultsThe magnitude of LTP 40 minutes after induction was predictive of long-term memory performance. Additionally, the BDNF Met allele was associated with both reduced LTP and reduced memory performance.\n\nConclusionsThe current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.

neuroscience↗

bioRxiv2018

No Evidence for Systematic White Matter Correlates of Dyslexia and Dyscalculia

Learning disabilities such as dyslexia, dyscalculia and their comorbid manifestation are prevalent, affecting as much as fifteen percent of the population. Structural neuroimaging studies have indicated that these disorders can be related to differences in white matter integrity, although findings remain disparate. In this study, we used a unique design composed of individuals with dyslexia, dyscalculia, both disorders and controls, to systematically explore differences in fractional anisotropy across groups using diffusion tensor imaging. Specifically, we focused on the corona radiata and the arcuate fasciculus, two tracts associated with reading and mathematics in a number of previous studies. Using Bayesian hypothesis testing, we show that the present data favor the null model of no differences between groups for these particular tracts--a finding that seems to go against the current view but might be representative of the disparities within this field of research. Together, these findings suggest that structural differences associated with dyslexia and dyscalculia might not be as reliable as previously thought, with potential ramifications in terms of remediation.

neuroscience↗

bioRxiv2018

No Evidence for Systematic White Matter Correlates of Dyslexia: An Activation Likelihood Estimation Meta-Analysis

Dyslexia is a prevalent neurodevelopmental disorder, characterized by reading and spelling difficulties. Beyond the behavioral and functional correlates of this condition, a growing number of studies have explored structural differences between individuals with dyslexia and typically developing individuals. To date, findings remain disparate - some studies suggest differences in fractional anisotropy (FA), an indirect measure of white matter integrity, whereas others do not identify significant disparities. Here, we synthesized the existing literature on this topic by conducting a meta-analysis of Diffusion Tensor Imaging (DTI) studies investigating white matter correlates of dyslexia via voxel-based analyses (VBA) of FA. Our results showed no reliable clusters underlying differences between dyslexics and typical individuals, after correcting for multiple comparisons (false discovery rate correction). Because group comparisons might be too coarse to yield subtle differences, we further explored differences in FA as a function of reading ability, measured on a continuous scale. Consistent with our initial findings, reading ability was not associated with reliable differences in white matter integrity. These findings nuance the current view of profound, structural differences underlying reading ability and its associated disorders, and suggest that their neural correlates might be more subtle than previously thought.

neuroscience↗