14 research outputs found
Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function
Seafood Consumption, Omega-3 Fatty Acids Intake, and Life-Time Prevalence of Depression in the PREDIMED-Plus Trial
Background: The aim of this analysis was to ascertain the type of relationship between fish
and seafood consumption, omega-3 polyunsaturated fatty acids (Ï-3 PUFA) intake, and depression
prevalence. Methods: Cross-sectional analyses of the PREDIMED-Plus trial. Fish and seafood
consumption and Ï-3 PUFA intake were assessed through a validated food-frequency questionnaire.
Self-reported life-time medical diagnosis of depression or use of antidepressants was considered
as outcome. Depressive symptoms were collected by the Beck Depression Inventory-II. Logistic
regression models were used to estimate the association between seafood products and Ï-3 PUFA
consumption and depression. Multiple linear regression models were fitted to assess the association
between fish and long-chain (LC) Ï-3 PUFA intake and depressive symptoms. Results: Out of
6587 participants, there were 1367 cases of depression. Total seafood consumption was not associated
with depression. The odds ratios (ORs) (95% confidence intervals (CIs)) for the 2nd, 3rd, and 4th
quintiles of consumption of fatty fish were 0.77 (0.63â0.94), 0.71 (0.58â0.87), and 0.78 (0.64â0.96),
respectively, and p for trend = 0.759. Moderate intake of total LC Ï-3 PUFA (approximately
0.5â1 g/day) was significantly associated with a lower prevalence of depression. Conclusion: In our
study, moderate fish and LC Ï-3 PUFA intake, but not high intake, was associated with lower odds
of depression suggesting a U-shaped relationship
Functional characterization of ribosomal P1/P2 proteins in human cells
International audienceThe stalk is a large ribosomal subunit domain that regulates translation. In this study, the role of the ribosomal stalk P proteins in modulating ribosomal activity has been investigated in human cells using RNAi. A strong down-regulation of P2 mRNA and a drastic reduction of P2 protein in a stable human cell line was achieved using a Dox-inducible system. Interestingly, the amount of P1 protein was similarly reduced in these cells, in contrast to the expression of P1 mRNA. The loss of P1/P2 proteins produced a reduction in the growth rate of these cells, as well as an altered polysome pattern with reduced translation efficiency but without affecting the free 40S/60S subunit ratio. A decrease in the ribosomal subunit joining capacity was also observed. These data indicate that P1/P2 proteins modulates cytoplasmic translation by influencing the interaction between subunits, thereby regulating the rate of cell proliferation
Tricyclic Antidepressants Inhibit the Ca2+-Dependent ATPase Activity from Plasma Membrane
Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis
Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies
Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment
VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.Fil: Salpietro, Vincenzo. UniversitĂ degli Studi di Genova; Italia. University College London; Estados UnidosFil: Malintan, Nancy T.. UniversitĂ degli Studi di Genova; ItaliaFil: Llano Rivas, Isabel. Hospital Universitario Cruces; EspañaFil: Spaeth, Christine G.. University of Cincinnati; Estados UnidosFil: Efthymiou, Stephanie. University College London; Estados UnidosFil: Striano, Pasquale. Istituto Giannina Gaslini; Italia. University of Genoa; ItaliaFil: Vandrovcova, Jana. University College London; Estados UnidosFil: Cutrupi, Maria Concetta. University of Messina; ItaliaFil: Chimenz, Roberto. University of Messina; ItaliaFil: David, Emanuele. Papardo University Hospital; ItaliaFil: Di Rosa, Gabriella. University of Messina; ItaliaFil: Marce Grau, Anna. University Hospital Vall dâHebron; EspañaFil: Raspall Chaure, Miquel. University Hospital Vall dâHebron; EspañaFil: Martin Hernandez, Elena. Hospital 12 de Octubre; EspañaFil: Zara, Federico. Istituto Giannina Gaslini; ItaliaFil: Minetti, Carlo. Istituto Giannina Gaslini; ItaliaFil: Bello, Oscar Daniel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias MĂ©dicas. Instituto de HistologĂa y EmbriologĂa de Mendoza Dr. Mario H. Burgos; ArgentinaFil: De Zorzi, Rita. UniversitĂ degli Studi di Trieste; ItaliaFil: Fortuna, Sara. UniversitĂ degli Studi di Trieste; ItaliaFil: Dauber, Andrew. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Alkhawaja, Mariam. No especifĂca;Fil: Sultan, Tipu. Institute of Child Health and The Childrenâs Hospital Lahore; PakistĂĄnFil: Mankad, Kshitij. Great Ormond Street Hospital for Children; Reino UnidoFil: Vitobello, Antonio. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Thomas, Quentin. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Tran Mau Them, Frederic. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Faivre, Laurence. Hospital dâEnfants, Dijon; Francia. Center Hospitalier Universitaire Dijon Bourgogne; FranciaFil: Martinez Azorin, Francisco. No especifĂca;Fil: Prada, Carlos E.. University of Cincinnati; Estados UnidosFil: Macaya, Alfons. University Hospital Vall dâHebron; Españ
Mediterranean diet and quality of life: baseline cross-sectional analysis of the PREDIMED-PLUS trial
We assessed if a 17-item score capturing adherence to a traditional Mediterranean diet
(MedDiet) was associated with better health-related quality of life among older Spanish men and women with overweight or obesity harboring the metabolic syndrome. We analyzed baseline data from 6430 men and women (age 55â70 years) participating in the PREDIMED-Plus study. PREDIMED-Plus is a multi-centre randomized trial testing an energyrestricted MedDiet combined with promotion of physical activity and behavioral therapy for primary cardiovascular prevention compared to a MedDiet alone. Participants answered a 36-item questionnaire about health-related quality of life (HRQoL) and a 17-item questionnaire that assessed adherence to an MedDiet. We used ANCOVA and multivariableadjusted linear regression models to compare baseline adjusted means of the quality of life scales according to categories of adherence to the MedDiet. Higher adherence to the MedDiet was independently associated with significantly better scores in the eight dimensions of HRQoL. Adjusted differences of > = 3 points between the highest and the lowest dietary adherence groups to the MedDiet were observed for vitality, emotional role, and mental health and of > = 2 points for the other dimensions. In conclusion, this study shows a positive association between adherence to a MedDiet and several dimensions of quality of life
RNA-Binding Proteins Impacting on Internal Initiation of Translation
RNA-binding proteins (RBPs) are pivotal regulators of all the steps of gene expression. RBPs govern gene regulation at the post-transcriptional level by virtue of their capacity to assemble ribonucleoprotein complexes on certain RNA structural elements, both in normal cells and in response to various environmental stresses. A rapid cellular response to stress conditions is triggered at the step of translation initiation. Two basic mechanisms govern translation initiation in eukaryotic mRNAs, the cap-dependent initiation mechanism that operates in most mRNAs, and the internal ribosome entry site (IRES)-dependent mechanism activated under conditions that compromise the general translation pathway. IRES elements are cis-acting RNA sequences that recruit the translation machinery using a cap-independent mechanism often assisted by a subset of translation initiation factors and various RBPs. IRES-dependent initiation appears to use different strategies to recruit the translation machinery depending on the RNA organization of the region and the network of RBPs interacting with the element. In this review we discuss recent advances in understanding the implications of RBPs on IRES-dependent translation initiation