Biology subjects

Moreau, D.

Publications and source records attributed to Moreau, D..

5 recordsLinked to original sources

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↗