Le syndrome de l'X fragile : Une protéine absente et 1001 ARNm déboussolés

Le syndrome du X fragile, première cause de retard mental héréditaire, est une maladie monogénique liée au chromosome X. Le syndrome est causé par l’inactivation du gène Fragile Mental Retardation 1(FMR1) entraînant l’absence de la protéine FMRP dont le rôle présumé est de coordonner le devenir et la traduction d’un grand nombre d’ARNm. Toutefois, s’il est actuellement admis que FMRP se comporte comme un répresseur de la traduction dans certaines conditions expérimentales, et malgré les nombreuses publications sur le sujet, nous devons nous rendre à l’évidence que les fonctions réelles de FMRP sont encore mal connues. De plus, l’existence de deux protéines FXR1P et FXR2P, homologues à FMRP, suggère que la fonction de FMRP est bien plus complexe que celle imaginée à l’origine. Nous limitons les propos de cet article à l’état actuel des connaissances concernant le rôle de FMRP dans l’adressage des ARNm, ainsi qu’aux conséquences possibles de l’absence de FMRP sur le transport et la traduction des ARNm dans les cellules pourvues d’arborescences et de prolongements que sont les neurones.Fragile X syndrome is the most common form of inherited mental retardation. This X-linked disease is due to transcriptional silencing of the Fragile Mental Retardation 1 (FMR1) gene and the absence of its gene product, FMRP. This protein is an RNA-binding protein present in mRNP complexes associated with the translation machinery and is thought to be a key player in the control of mRNA transport in neurons. However, the exact role of FMRP in translation remains unclear. Two homologous proteins, FXR1P and FXR2P, are also found in RNP complexes containing FMRP, suggesting that FMRP’s functions are much more complex than first thought. The molecular mechanisms altered in cells lacking FMRP still remain to be elucidated, as well as the putative roles of FXR1P and FXR2P as compensatory molecules. Here, we review the various possible functions of FMRP in RNA localization and transport in highly differentiated cells containing dendritic extensions such as neurons

The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers

BACKGROUND: The rhomboid family of polytopic membrane proteins shows a level of evolutionary conservation unique among membrane proteins. They are present in nearly all the sequenced genomes of archaea, bacteria and eukaryotes, with the exception of several species with small genomes. On the basis of experimental studies with the developmental regulator rhomboid from Drosophila and the AarA protein from the bacterium Providencia stuartii, the rhomboids are thought to be intramembrane serine proteases whose signaling function is conserved in eukaryotes and prokaryotes. RESULTS: Phylogenetic tree analysis carried out using several independent methods for tree constructions and the corresponding statistical tests suggests that, despite its broad distribution in all three superkingdoms, the rhomboid family was not present in the last universal common ancestor of extant life forms. Instead, we propose that rhomboids evolved in bacteria and have been acquired by archaea and eukaryotes through several independent horizontal gene transfers. In eukaryotes, two distinct, ancient acquisitions apparently gave rise to the two major subfamilies, typified by rhomboid and PARL (presenilins-associated rhomboid-like protein), respectively. Subsequent evolution of the rhomboid family in eukaryotes proceeded by multiple duplications and functional diversification through the addition of extra transmembrane helices and other domains in different orientations relative to the conserved core that harbors the protease activity. CONCLUSIONS: Although the near-universal presence of the rhomboid family in bacteria, archaea and eukaryotes appears to suggest that this protein is part of the heritage of the last universal common ancestor, phylogenetic tree analysis indicates a likely bacterial origin with subsequent dissemination by horizontal gene transfer. This emphasizes the importance of explicit phylogenetic analysis for the reconstruction of ancestral life forms. A hypothetical scenario for the origin of intracellular membrane proteases from membrane transporters is proposed

FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure

FRAXE is a form of mild to moderate mental retardation due to the silencing of the FMR2 gene. The cellular function of FMR2 protein is presently unknown. By analogy with its homologue AF4, FMR2 was supposed to have a role in transcriptional regulation, but robust evidences supporting this hypothesis are lacking. We observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternatively spliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein, which might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure

Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The “Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)” is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS0002904

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry. © 2022 The AuthorsImmuno-Génétique, Inflammation, retro-Virus, Environnement : de l'étiopathogénie des troubles psychotiques aux modèles animauxRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

Caractérisation de la protéine PARL, le prototype d'une nouvelle sous-famille de sérine-protéases assurant la protéolyse intramembranaire régulée

La protéine PARL (Presenilins-Associated Rhomboid-Like protein) est une nouvelle protéine présentant des similarités significatives avec la famille de régulateurs développementaux de Drosophila melanogaster Rhomboid, assurant la protéolyse intramembranaire régulée (RIP). La RIP est un processus par lequel certaines protéines transmembranaires sont clivées à l'intérieur de la membrane pour libérer un domaine cytoplasmique actif. Pour valider l'homologie fonctionnelle entre PARL et Rhomboid-1, nous avons conduit une analyse phylogénétique complète portant sur l'ensemble des membres de la super-famille Rhomboid. Cette étude révèle que cette famille est présente à tous les niveaux évolutifs et que tous ses membres, y compris PARL, sont des sérine-protéases catalysant la RIP. Nos études immunohistochimiques démontrent que le profil d'expression de PARL est régulé dynamiquement au cours du développement postnatal du cerveau de souris. D'autre part, PARL est sélectivement exprimée dans les cellules mitotiques et les neurones indifférenciés, mais pas dans les cellules gliales. De plus, chez l'adulte, l'expression de PARL est restreinte aux zones de neurogenèse active tout au long de la vie de l'animal. L'ensemble de ces résultats indique que l'expression de PARL commence durant la phase proliférative des précurseurs neuronaux, continue dans les étapes précoces de la différenciation neuronale et qu'elle est ensuite régulée négativement au cours de la différenciation. Nous proposons donc que l'activité de RIP-protéase de la protéine PARL joue un rôle essentiel dans l'engagement de la cellule vers la destinée neuronale et dans la neurogenèse

Cytokine changes associated with the maternal immune activation (MIA) model of autism: A penalized regression approach.

Maternal immune activation (MIA) during pregnancy induces a cytokine storm that alters neurodevelopment and behavior in the progeny. In humans, MIA increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD). In mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C)) to pregnant dams. Although the murine model of MIA has been extensively studied, it is not clear whether MIA results in cytokine changes in the progeny at early postnatal stages. Further, the murine model of MIA suffers from a lack of reproducibility and high inter-individual variability. Multivariable (MV) statistical analysis is widely used in human studies to control for confounders and covariates such as sex, age and exposure to environmental factors. We therefore reasoned that animal studies in general and studies on the MIA model in particular could benefit from MV analyses to account for complex phenotype interactions and high inter-individual variability. Here, we used MV statistical analysis to identify cytokines associated with MIA after adjustment for covariates. Besides confirming the association between previously described variables and MIA, we identified new cytokines that could play a role in behavioural alterations in the progeny during the early postnatal period