Biology subjects

Simonneau, M.

Publications and source records attributed to Simonneau, M..

8 recordsLinked to original sources

bioRxiv2022

AUTS2 expression within mammalian lineage: a predictor of neural networks involved in Autism Spectrum Disorders

Autism susceptibility gene 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant neurological syndrome with ASD-like (Autism Spectrum Disorder-like) features. The AUTS2 syndrome phenotype includes borderline to severe intellectual disability (ID), microcephaly and mild dysmorphic traits. Specific ASD-like features, including obsessive or ritualistic behaviours, are frequently displayed, although sociability is largely unaffected. Syndrome severity is worse when mutations are present in the 3 region (exons 9-19) of the AUTS2 gene. AUTS2 is also associated with alcohol consumption, heroin dependence, schizophrenia and dyslexia, using GWAS studies. Our working hypothesis is that AUTS2 expression during mammalian evolution can be instrumental to predict phenotypes linked to the disease. For that, we studied brain In Situ Hybridization (ISH) data in mouse, marmoset, human embryo and fetuses and sequences data of Neanderthal, Denisovan and modern humans. Developmental mouse brain expression is found in neocortex, hippocampus, thalamus, tegmentum and cerebellum suggesting a link linked with cognition, stereotypies and perseverative behaviors. Expression in amygdala and claustrum found in marmoset extend these phenotypes to anxiety and higher-order cognitive processes. In human embryos (8 weeks) and fetuses (15- and 19-weeks), we found AUTS2 expression in similar regions but also in medial, lateral and caudal ganglionic eminence, that are involved in the diversity of interneurons found in neocortex, hippocampus and striatum. Sequence comparison of AUTS2 locus in Neanderthal, Denisova and modern human reveals novel sites in regulatory regions of AUTS2. Altogether, these results suggest that ISH distribution along mammals is a novel phenotype-related biomarker useful for translational research.

neuroscience↗

bioRxiv2022

AUTS2 gene dosage affects synaptic AMPA receptors via a local dendritic spine AUTS2-TTC3-AKT-mTORC1 signaling dysfunction

The Human 1.2-Mb AUTS2 locus on chromosome 7q11.22 encodes a 1259-aa full-length protein, and a 711-aa C-terminal isoform. Functions of these AUTS2 proteins are only partly known. The major traits found in patients displaying AUTS2 locus mutations are Intellectual Disabilities, microcephaly attention deficit hyperactivity disorder (ADHD) (54%), and autistic traits. Furthermore, AUTS2 common variants were recently found associated to alcohol consumption and dyslexia using GWAS approaches. Auts2 localizes mainly in cell nuclei. We evidenced by super-resolution that Auts2 is present in dendritic spines. Auts2 interacts with Ttc3, the Akt2 E3 ligase, and negatively regulates Akt2 ubiquitination. Auts2 haploinsufficiency affects Akt/mTorc1 pathway with a decrease in AMPA and NMDA receptor subunits and in synaptic currents. Akt2 injection in postsynaptic neurons is sufficient to reverse changes in synaptic currents generated by Auts2 haploinsufficiency. Using chromosome engineering based on targeted meiotic recombination, we generated two mouse models with Auts2 locus deletion and duplication. Deleted Auts2 locus mice display stereotypies (rearing), perseveration and abnormal recognition memory. Duplicated Auts2 locus mice display similar perseveration and abnormal recognition memory but also a decrease in cued and contextual fear memory. Gene dosage induce changes in brain sub-region neuronal networks. In the thalamo-lateral amygdala pathway linked to cued fear memory, we found synaptic impairments linked to AMPA receptors, with a specific decrease in pAKT/total AKT ratio in duplicated Auts2 mice. Altogether, our study thereby provides a novel mechanistic and potentially therapeutic understanding of synaptic AKT/mTORC1 deregulated signaling and its related behavioral and cognitive phenotypes.

neuroscience↗

bioRxiv2022

BigNeuron: A resource to benchmark and predict best-performing algorithms for automated reconstruction of neuronal morphology

BigNeuron is an open community bench-testing platform combining the expertise of neuroscientists and computer scientists toward the goal of setting open standards for accurate and fast automatic neuron reconstruction. The project gathered a diverse set of image volumes across several species representative of the data obtained in most neuroscience laboratories interested in neuron reconstruction. Here we report generated gold standard manual annotations for a selected subset of the available imaging datasets and quantified reconstruction quality for 35 automatic reconstruction algorithms. Together with image quality features, the data were pooled in an interactive web application that allows users and developers to perform principal component analysis, t-distributed stochastic neighbor embedding, correlation and clustering, visualization of imaging and reconstruction data, and benchmarking of automatic reconstruction algorithms in user-defined data subsets. Our results show that image quality metrics explain most of the variance in the data, followed by neuromorphological features related to neuron size. By benchmarking automatic reconstruction algorithms, we observed that diverse algorithms can provide complementary information toward obtaining accurate results and developed a novel algorithm to iteratively combine methods and generate consensus reconstructions. The consensus trees obtained provide estimates of the neuron structure ground truth that typically outperform single algorithms. Finally, to aid users in predicting the most accurate automatic reconstruction results without manual annotations for comparison, we used support vector machine regression to predict reconstruction quality given an image volume and a set of automatic reconstructions.

bioinformatics↗

bioRxiv2021

Impact of α-synuclein fibrillar strains and β-amyloid assemblies on mouse cortical neurons endo-lysosomal logistics

Endosomal transport and positioning are involved in establishing neuronal compartment architecture, dynamics and function, contributing to neuronal intracellular logistics. Furthermore, endo-lysosomal dysfunction has been identified as a common mechanism in neurodegenerative diseases. Here, we analyzed endolysosomal transport following the external application of -synuclein (-syn) fibrillar polymorphs, {beta}-amyloid (A{beta}) fibrils and oligomers on primary cultures of mouse cortical neurons. We used a simple readout to measure this transport: the spontaneous endocytosis of fluorescent nanodiamonds -- a perfectly stable nano-emitter -- in cultured neurons. We then performed a high-throughput automatic extraction and quantification of the directed motions of these nanodiamonds. -syn fibrillar polymorphs, A{beta} fibrils and oligomers halved the proportion of nanodiamonds transported along microtubules, but only slightly decreased their interactions with cortical neurons. This large decrease in endosomal transport would be expected to have a huge impact on neuronal homeostasis. We then assessed lysosomal dynamics with Lysotracker. The exposure of neurons to A{beta} oligomers led to an increase in the number of lysosomes, a decrease in the fraction of moving lysosomes and an increase in their size, reminiscent of findings for the APP transgenic model of Alzheimers disease. We then analyzed the effect of -syn fibrillar polymorphs, A{beta} fibrils and oligomers on endosomal and lysosomal transport and quantified the directed transport of these assemblies within cortical neurons. We report different impacts on endosomal and lysosomal transport parameters and differences in trajectory length for cargoes loaded with pathogenic protein assemblies. Our results suggest that the internalization and transport of intraneuronal pathogenic protein aggregates are potential targets for novel neuroprotective treatment strategies. Significance StatementNeurodegenerative diseases (NDs) are characterized by the deposition of protein aggregates with broad-range neuronal toxicity. Defects of endolysosomal trafficking are increasingly being seen as key pathological features of NDs, probably contributing to synaptic dysfunction and ultimate neuronal death. We used fast fluorescence videomicroscopy to investigate endosomal and lysosomal dynamics in the branches of mouse cortical neurons in primary cultures following the application of -syn fibrillar polymorphs (fibrils and ribbons) and A{beta} assemblies (oligomers and fibrils). We provide new insight into the differential effects of these pathogenic protein assemblies on endosomal and lysosomal transport, and reveal differences in the transport characteristics of the compartments loaded with these protein assemblies relative to endosomes.

neuroscience↗

bioRxiv2019

Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease

Intellectual disability (ID) found in Down syndrome (DS), which is characterized by an extra copy of 234 genes on Chr21 is poorly understood. We first used two DS mouse models that either display an extra copy of the Dyrk1A gene or of the mouse Chr16 syntenic region. Exome sequencing of transcripts deregulated in embryonic hippocampus uncovers enrichment in genes involved in chromatin and synapse respectively. Using large-scale yeast two-hybrid screen (154 distinct screens) of human brain library containing at least 107 independent fragments, we identified 3,636 novel protein-protein interactions with an enrichment of direct interactors of both Chromosome 21(Hsa21) baits and rebounds in ID-related genes. Using proximity ligation assays, we identified that Hsa21-encoded proteins are located at the dendritic spine postsynaptic density in a protein network located at the dendritic spine post synapse. We located Hsa21 DYRK1A and DSCAM that confers a [~] 20-fold increase in Autism Spectrum Disorders (ASDs), in this postsynaptic network. We found that a DSCAM intracellular domain binds either DYRK1A or DLGs that are multimeric scaffolds for the clustering of receptors, ion channels, and associated signaling proteins. The DYRK1A-DSCAM interaction is conserved from drosophila to humans. The identified postsynaptic.network is enriched in ARC-related synaptic plasticity, ASDs and Late-Onset Alzheimer Disease. Altogether, these results emphasize links between DS and brain diseases with complex genetics.

neuroscience↗

bioRxiv2019

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

Autism Spectrum Disorders (ASDs) are a heterogeneous collection of neurodevelopmental disorders with a strong genetic basis. Recent studies identified that a single hit of either a de novo or transmitted gene-disrupting, or likely gene-disrupting, mutation in a subset of 65 strongly associated genes can be sufficient to generate an ASD phenotype. We took advantage of consanguineous families with an ASD proband to evaluate this model. By a genome-wide homozygosity mapping of ten families with eleven children displaying ASD, we identified a linkage region of 133 kb in five families at the 3p14.2 locus that includes FEZF2 with a LOD score of 5.8 suggesting a founder effect. Sequencing FEZF2 revealed a common deletion of four codons. However, the damaging FEZF2 mutation did not appear to be sufficient to induce the disease as non-affected parents also carry the mutation and, similarly, Fezf2 knockout mouse embryos electroporated with the mutant human FEZF2 construct did not display any obvious defects in the corticospinal tract, a pathway whose development depends on FEZF2. We extended the genetic analysis of these five FEZF2-linked families versus five FEZF2 non-linked families by studying de novo and transmitted copy number variation (CNV) and performing Whole Exome Sequencing (WES). We identified damaging mutations in the subset of 65 genes strongly associated with ASD whose co-expression analysis suggests an impact on the prefrontal cortex during the mid-fetal periods. From these results, we propose that both FEZF2 deletion and multiple hits in the repertoire of these 65 genes are necessary to generate an ASD phenotype.\n\nSignificance StatementThe human neocortex is a highly organized laminar structure with neuron positioning and identity of deep-layer cortical neurons that depend on key transcription factors, such as FEZF2, SATB2, TSHZ3 and TBR1. These genes have a specific spatio-temporal pattern of expression in human midfetal deep cortical projection neurons and display mutations in patients with Autism Spectrum Disorder (ASD). Here, we identified a linkage region involving FEZF2 gene in five consanguineous families with an ASD proband. For these FEZF2-allele linked probands, we identified a four-codon deletion in FEZF2 and damaging mutations in other high-risk ASD genes, that exhibit regional and cell type-specific convergence in neocortical deep-layer excitatory neurons, suggesting a multi-hit genomic architecture of ASD in these consanguineous families.

neuroscience↗

bioRxiv2019

DYRK1A up-regulation specifically impairs a presynaptic form of long-term potentiation

Chromosome 21 DYRK1A kinase has long been associated with a variety of psychiatric diseases including Down Syndrome. We previously showed that Dyrk1A interacts with SWI/SNF (SWItch/Sucrose Non-Fermentable) nucleosome remodeling complex inducing expression changes of genes encoding key neuronal proteins. However, the functional impact of this kinase at the synapse level remains unclear. We studied a mouse model that incorporated the YAC 152F7 (570 kb) encoding six chromosome 21 genes including DYRK1A. We found that DYRK1A Interacts with the key chromatin remodelers EP300 and CREBBP. Moreover, we observed changes in the transcriptional levels of genes encoding presynaptic proteins involved in glutamate vesicle exocytosis, namely Rims1, Munc13-1, Syn2, Rab3A. This result prompted us to investigate the two main forms of long-term potentiation (LTP) required for learning and memory: the (N-methyl d-aspartate) receptor-dependent postsynaptic form versus the glutamate release-dependent presynaptic form. Interestingly, extracellular electrophysiological recordings in hippocampal slices of the YAC mouse line revealed that only the presynaptic forms of plasticity were impacted, leaving the post-synaptic form of plasticity intact. T o refine our findings, we used a mouse BAC 189N3 (152 kb) line that only triplicate the gene Dyrk1A. Again, we found that this presynaptic form of LTP is also impaired in this mouse line. This result demonstrates that abnormal up-regulation of Dyrk1A alone is sufficient to inhibit specifically the presynaptic forms of LTP. Altogether, our results suggest that impairment of DYRK1A gene dosage may impact memory precision, and therefore reinforce our mechanistic understanding of the cognitive impairment detected in this mouse model.

neuroscience↗

bioRxiv2018

BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal cortex-dentate gyrus pathway and related hippocampal multi-scale impairments

Genetic factors are known to contribute to Late Onset Alzheimers disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood. To translate genetic risk of Alzheimers disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a [~]195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex. These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.

neuroscience↗