Curr Biol

Efference copies are neural replicas of motor outputs used to anticipate the sensory consequences of a self-generated motor action or to coordinate neural networks involved in distinct motor behaviors. An established example of this motor-to-motor coupling is the efference copy of the propulsive motor command, which supplements classical visuo-vestibular reflexes to ensure gaze stabilization during amphibian larval locomotion. Such feedforward replica of spinal pattern-generating circuits produces a spino-extraocular motor coupled activity that evokes eye movements, spatiotemporally coordinated to tail undulation independently of any sensory signal. Exploiting the developmental stages of the frog, studies in metamorphing Xenopus demonstrated the persistence of this spino-extraocular motor command in adults and its developmental adaptation to tetrapodal locomotion. Here, we demonstrate for the first time the existence of a comparable locomotor-to-ocular motor coupling in the mouse. In neonates, ex vivo nerve recordings of brainstem-spinal cord preparations reveal a spino-extraocular motor coupled activity similar to the one described in Xenopus. In adult mice, trans-synaptic rabies virus injections in lateral rectus eye muscle label cervical spinal cord neurons closely connected to abducens motor neurons. Finally, treadmill-elicited locomotion in decerebrated preparations evokes rhythmic eye movements in synchrony with the limb gait pattern. Overall, our data are evidence for the conservation of locomotor-induced eye movements in vertebrate lineages. Thus, in mammals as in amphibians, CPG-efference copy feedforward signals might interact with sensory feedback to ensure efficient gaze control during locomotion.Corrélats neurophysiologiques de l'évolution et du développement des stratégies de stabilisation du regard pendant la locomotion chez les vertébrésUniversité de Pari

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI-deficient patient\u27s stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Etude quantitative de la geometrie, des proprietes electrotoniques et de l'ultrastructure des dentrites de motoneurones craniens : une approche de la fonction integrative du neurone

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Differential effects of spinal cord transection on glycinergic and GABAergic synaptic signaling in sub-lesional lumbar motoneurons

International audienceThis review takes stock on the impact of complete spinal cord transection (SCT) on the plasticity of inhibitory synaptic transmission on sub-lesional lumbar motoneurons (MNs), differentiating between studies in neonate and adult rats.After neonatal SCT, normal maturational up-regulation of glycine receptors was observed. On the other hand, the developmental downregulation of the GABAA receptors, as well as the up-regulation of the co-transporter KCC2 were prevented, but not the normal decrease of NKCC1.In adult SCT rats, glycinergic synaptic transmission, which is the major contributor to spinal MNs inhibition in adulthood, had normal control levels 2 months post-injury. On the other hand, the GABAergic transmission was altered through an up-regulation of the pre-signaling levels and a down-regulation in the density of post synaptic receptors. KCC2 membrane expression was down-regulated at all post-injury times tested (24h to 4 months), thereby depolarizing the Cl− equilibrium potential and reducing the strength of postsynaptic inhibition.The preservation of glycinergic pre- and post signaling is probably a key factor in the success of locomotor rehabilitation programs in adult SCT rats. However, these data highlight the need to develop strategies to restore KCC2 levels in lumbar MNs, to stabilize the excitation/inhibition balance, which is essential to the effective control of skeletal muscle activity

Les instruments juridiques de la recherche publique

Available from INIST (FR), Document Supply Service, under shelf-number : RL 379 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLECommissariat General du Plan, 75 - Paris (France)FRFranc

Les instruments juridiques de la recherche publique

Available from INIST (FR), Document Supply Service, under shelf-number : RL 379 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLECommissariat General du Plan, 75 - Paris (France)FRFranc

Les instruments juridiques de la recherche publique

Available from INIST (FR), Document Supply Service, under shelf-number : RL 377 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc