Les microARNs sont une classe de petits ARNs non codants qui régulent l'expression des gènes via un mecanisme d'interference par ARN. Les microARNs humains sont produits par une série de réactions enzymatiques. En particulier, dans le cytoplasme le precurseur de miRNA (pre-miRNA) est reconnu et clivé par un complexe contenant l'enzyme RNAse III Dicer et plusieurs cofacteurs protéiques. La proteine TRBP (HIV TAR RNA binding protein) est l'un de ces cofacteurs et augmente la stabilité du complexe, influe sur la cinétique, la position du clivage et a role potentiel dans la reconnaissance du substrat et dans le transfet du produit vers le complexe RISC (RNA-induced silencing complex) effecteur de l'interference par ARN. TRBP est composé de 3 domaines de liaison aux ARN doubles brin (dsRBDs). La région d'interaction de TRBP avec les ARNs est composé des deux premiers dsRBDs liés par une région interdomaine non charactérizée. La présente étude rapporte la caractérisation biophysique in vitro de la région d'interaction avec les ARNs de TRBP dans l'état apo de TRBP ou dans l'état lié avec les deux precurseurs cytoplasmique successifs du microARN oncogène miR-155 comprenant la tige boucle pre-miR-155 et le duplex miR-155/miR-155* résultat du clivage de pre-miR-155 par Dicer. L'étude montre que la région d'intéraction de TRBP avec les ARNs est monomerique, est composée de deux dsRBDs independants en solution et que la région interdomaine de 60 résidus est flexible. Le premier dsRBD, non caractérisé précédement en solution est le siège d'un equilibre plié/déplié integral dans une grande gamme de conditions physico-chimiques. Les deux premiers dsRBDs de TRBP peuvent interagir avec un même precurseur de microARN et deux régions d'interaction de TRBP avec les ARNs peuvent interagir avec un même precuseur. La région d'interaction de TRBP avec les ARNs interagit avec pre-miR-155 et le duplex miR-155/miR-155* avec des affinités très similaires. Dans le complexe avec une région d'interaction de TRBP avec les ARN liée à pre-miR-155 ou au duplexe miR-155/miR-155*, aucune indice de contact entre les deux dsRBDs n'a été detecté et la protéine interagit avec les deux precurseurs par la même surface d'interaction. Les informations récoltées suggèrent que TRBP peut jouer un rôle avant et après le clivage des pre-miARN par Dicer, notamment dans le complexe de chargement de RISC. / MicroRNAs (miRNA) are a class of small non-coding RNAs that regulate gene expression through RNA interference (RNAi). Human miRNAs are generated via a series of enzymatic processing steps. In particular, in the cytoplasm, the precursor miRNA (pre-miRNA) is recognized and cleaved by a complex containing the RNase III enzyme Dicer and several non-catalytic accessory proteins. HIV TAR element-binding protein (TRBP) is a constituent of the Dicer complex, which augments complex stability, has effect on the cleavage kinetics and on the cleavage site and potentially functions in substrate recognition and product transfer to the RNA-induced silencing complex (RISC). TRBP is composed of three double stranded RNA binding domains (dsRBDs). The RNA binding region of TRBP is composed of the first two dsRBDs and an uncharacterized interdomain region. The present study reports the in vitro biophysical characterization of the RNA binding region of TRBP in the apo state and in the RNA bound state with the two successive cytoplasmic precursors of the oncogenic human microRNA miR-155, the hairpin pre-miR-155 and the related Dicer product miR-155/miR-155* duplex. The study shows that the RNA binding region of TRBP is monomeric and comprises two independent double-stranded RNA-binding domains connected by a 60 residues flexible linker. The first dsRBD, uncharacterized previously in solution, undergoes a full folding/unfolding equilibrium in a wide range of physico-chemical conditions. The two first dsRBDs of TRBP can interact with one microRNA precursor and two RNA binding regions can interact with one precursor molecule. The RNA-binding region of TRBP interacts with both pre-miR-155 and miR-155/miR-155* duplex with similar affinities. In the complex with one RNA binding region of TRBP bound to either pre-miR-155 or miR-155/miR-155* duplex, no evidence of contact between the two dsRBDs were observed and the protein interacts with both precursors via the same protein binding surface. The data presented here suggest that the RNA binding region of TRBP can play a role before and after processing of pre-miRNAs by Dicer, including in the RISC loading complex.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Several groups pointed out that miRNAs play a major role in several diseases, including cancer. This is assumed since the expression level of several miRNAs differs between normal and cancerous cells. Further, it has been shown that miRNAs are involved in cell proliferation and cell death. Because of this role it is suspected that miRNAs could serve as biomarkers to improve tumor classification, therapy selection, or prediction of survival. In this context, it is questioned, among other things, whether miRNA deregulations in cancer cells occur according to some pattern or in a rather random order. With this work we contribute to answering this question by adapting two approaches (Beerenwinkel et al. (J Comput Biol, 2005) and Höglund et al. (Gene Chromosome Canc, 2001)), developed to derive graph models of oncogenesis for chromosomal imbalances, to miRNA expression data and applying them to a breast cancer data set. Further, we evaluated the results by comparing them to results derived from randomly altered versions of the used data set. We could show that miRNA deregulations most likely follow a rough temporal order, i.e. some deregulations occur early and some occur late in cancer progression. Thus, it seems to be possible that the expression level of some miRNAs can be used as indicator for the stage of a tumor. Further, our results suggest that the over expression of mir-21 as well as mir-102 are initial events in breast cancer oncogenesis. Additionally, we identified a set of miRNAs showing a cluster-like behavior, i.e. their deregulations often occur together in a tumor, but other deregulations are less frequently present. These miRNAs are let-7d, mir-10b, mir-125a, mir-125b, mir-145, mir-206, and mir-210. Further, we could confirm the strong relationship between the expression of mir-125a and mir-125b.

According to the cancer stem cells (CSCs) hypothesis, CSCs are responsible for the treatment failures. CSCs are a subset of cells possessing stemness properties within the heterogeneous tumor mass. Therapeutic intervention on Wnt signaling is of our great interest because an aberrant Wnt signaling is an important driver to maintain the potency of CSCs. In nasopharyngeal carcinoma (NPC), deregulated expression of the Wnt signaling components is frequently observed. ICG-001 is a selective Wnt modulator (CBP antagonist) that specifically interrupts the interaction between β-catenin and CBP, thereby encourages the interaction between β-catenin and p300 and the subsequent differentiation and reduction of the CSCs subset. For this reason, the present study aimed to evaluate the therapeutic potential of ICG-001 in NPC. Results showed that ICG-001 inhibited both the migration of the NPC cells and the formation of tumor spheres. In the first part of the mechanistic studies (Chapter 3), ICG-001 was found to restore the expression of miR-150 in NPC cells. MiR-150 was further found to directly reduce CD44 expression and inhibit NPC cell migration. In the second part of the mechanistic studies (Chapter 4), ICG-001 was found to reduce the expression of Evi1 in NPC cells. The effect was accompanied with the inhibition of both the NPC cells migration and the tumor spheres formation. Two molecular axes, namely miR-96/Evi1/miR-449a and survivin/Evi1/miR-449a, were found to be involved in the inhibition of the tumor cell migration and spheroids formation. The therapeutic potential of using this CBP antagonist (ICG-001) in NPC, namely the in vitro and in vivo efficacy of ICG-001 combined with cisplatin, was examined (Chapter 5). Concurrent treatment of ICG-001 and cisplatin exhibited a synergistic inhibition on the in vitro growth and the tumor sphere forming capacity of NPC cells as well as the growth of NPC xenografts. Taken together, results presented in this thesis suggested that ICG-001 (PRI-724 is the analog of ICG-001 currently used in clinical trials) has a therapeutic potential in NPC.

Orientador: Adriana Souza Torsoni / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas / Made available in DSpace on 2018-08-24T18:35:57Z (GMT). No. of bitstreams: 1 Oliveira_RafaelaBenatti_M.pdf: 1191668 bytes, checksum: 30188f35804e6016d9ee2cffa54ee9d5 (MD5) Previous issue date: 2013 / Resumo: O consumo materno de uma dieta rica em gordura (HFD) durante a gestação e lactação está intimamente relacionada ao acúmulo de lipídios no fígado, a resistência à insulina e ao aumento de citocinas no soro, na prole jovem e na idade adulta. MicroRNAs (miRNAs) têm sido relacionados com a biossíntese do colesterol e no metabolismo dos ácidos graxos. Nós avaliamos a modulação da síntese hepática de ácidos graxos (de novo), as vias da beta-oxidação e a expressão dos microRNAs miR-122 e miR -370 em prole recém desmamados (d28) de mães alimentadas com HFD (grupo HFD-O) ou ração padrão (grupo SC-O) durante a gestação e lactação. Comparado com os camundongos SC-O, os camundongos HFD-O apresentaram um maior peso corpóreo, maior massa de tecido adiposo e eram intolerantes à glicose e insulina. HFD-O camundongos também apresentaram níveis séricos elevados de colesterol, triglicérides, ácidos graxos não esterificados e maior fosforilação hepática de IKK e JNK em comparação com camundongos SC-O. Os níveis das proteínas FAS, ACC e HMGCR foram semelhantes entre os camundongos HFD-O e SC-O, enquanto os níveis de RNAm e proteína da SCD1 foram mais abundantes nos camundongos HFD-O comparados com camundongos SC-O. Curiosamente, a expressão de RNAm de genes relacionados com a ?-oxidação, como a ACADVL CPT1 estavam diminuídos em camundongos HFD-O. Embora não observamos uma diferença nos níveis de HNF4? hepáticas, a expressão de miR -122 estava diminuída, e a expressão de miR-370 estava aumentada em HFD-O em comparação com camundongos SC-O. Alterações no metabolismo lipídico hepático foram acompanhados pelo aumento da deposição de triglicerídes em camundongos HFD-O. Em conjunto, os nossos resultados sugerem fortemente que o consumo materno de HFD afeta precocemente o metabolismo lipídico da prole de camundongos através da modulação da expressão de genes e miRNAs relacionados com a ?-oxidação hepática e que podem contribuir para as alterações metabólicas na vida adulta / Abstract: Maternal consumption of high-fat diet (HFD) during pregnancy and lactation is closely related to liver lipid accumulation, insulin resistance, and increased serum cytokines in offspring and into adulthood. MicroRNAs (miRNAs) have been implicated in cholesterol biosynthesis and fatty acid metabolism. We evaluated the modulation of hepatic fatty acid synthesis (de novo), beta-oxidation pathways and miR-122 and miR-370 expression in recently weaned offspring (d28) of mice dams fed HFD (group HFD-O) or standard chow (group SC-O) during pregnancy and lactation. Compared with SC-O mice, HFD-O mice weighed more, had a larger adipose tissue mass and were more intolerant to glucose and insulin. HFD-O mice also presented more serum cholesterol, triglycerides, non-esterified fatty acids and hepatic IKK and JNK phosphorylation compared with SC-O mice. Protein levels of FAS, ACC and HMGCR were similar in HFD-O and SC-O mice, whereas SCD1 mRNA and protein were more abundant in HFD-O mice compared with SC-O mice. Interestingly, mRNA expression of ?-oxidation-related genes ACADVL and CPT1 was decreased in HFD-O mice. Although we did not observe a difference in hepatic HNF4? levels, the expression of miR-122 was reduced but that of miR-370 was increased in HFD-O mice compared with that in SC-O mice. Changes in hepatic lipid metabolism were accompanied by increased triglyceride deposition in HFD-O mice. Taken together, our results strongly suggest that maternal consumption of HFD affects the early lipid metabolism of offspring by modulating the expression of hepatic ?-oxidation-related genes and miRNAs that can contribute to metabolic disturbances in adult life / Mestrado / Metabolismo e Biologia Molecular / Mestra em Ciências da Nutrição e do Esporte e Metabolismo

La mitochondrie est une organite ayant un rôle central dans le métabolisme énergétique de la cellule. Bien que la mitochondrie exprime son propre génome, plusieurs protéines et ARN non-codants issus du génome nucléaire sont nécessaires à la biogenèse et aux fonctions mitochondriales. Les microARNs (miRNAs) sont de petits ARN non-codants qui s'associent à la protéine Argonaute 2 (Ago2) pour moduler l'expression génique au niveau post-transcriptionnelle par ARN interférence. Classiquement, les miRNAs s’apparient à des sites de liaison complémentaires situés dans le 3’-UTR de l’ARNm cible. Nous faisons l'hypothèse que les miRNAs seraient impliqués dans la communication entre le noyau et la mitochondrie. Notre travail a donc porté sur l’étude du rôle des miRNAs dans le contexte de maladies génétiques caractérisées par une dysfonction mitochondriale. Nous avons choisi d’étudier l’ataxie de Friedreich, la plus fréquente des ataxies héréditaires, qui est causée par un déficit d’expression de la protéine mitochondriale frataxine (FXN). Nous avons montré qu'environ 90% de patients étaient homozygotes pour un haplotype spécifique des variants génétiques du 3'-UTR du gène FXN. Ce résultat a été retrouvé dans deux cohortes de patients indépendantes. Par une combinaison d’approche bioinformatique et d’expériences de co-transfections, nous avons montré que les miRNAs, et en particulier miR-124, ciblent les variants du 3’-UTR. En parallèle, nous avons évalué la possibilité que les miRNAs ciblent directement la mitochondrie. Pour cela, nous avons analysé l’expression des miRNAs dans des fractions d'ARN mitochondriale et cytosolique isolées à partir de mêmes cellules HeLa. Nous avons identifié une signature de 13 miRNAs spécifiquement enrichis dans la fraction d'ARN mitochondriale que nous avons appelé «mitomiRs». Nos prédictions ont révèle des fonctions spécifiques de ces mitomiRs à la mitochondrie, y compris la modulation de l'activité de la chaîne respiratoire. Nous avons également montré une localisation de la protéine Ago2 à l’espace inter-membranaire mitochondriale.Notre travail définit ainsi les miRNAs et Ago2 comme un nouveau niveau de communication entre le noyau et les mitochondries. Nous discutons de la possibilité que la mitochondrie agisse comme acteur du ARN interférence ou plutôt comme organite cible. Notre travail ouvre la voie à un nouveau domaine de recherche, qui pourrait avoir une utilité thérapeutique pour palier les dysfonctions mitochondriales. / Mitochondria are organelles that have a central role in the energetic metabolism of the cell. Although mitochondria express their own genome, they rely on the expression of the nuclear genome for their biogenesis and function. microRNAs (miRNAs) are small non-coding RNAs that associate with Argonaute 2 (Ago2) protein to regulate gene expression post-transcriptionallythrough RNA interference. The ‘classic’ view of RNA interference describes the pairing of miRNAs with complementary binding sites within the 3’untranslated region (3’-UTR) of the target mRNA. We hypothesized that miRNAs might be instrumental to the cross-talk between the nucleus and the mitochondria. In the first part, we assessed the role of miRNAs in the context of a rare genetic disease involving mitochondrial dysfunction. We focused on Friedreich's ataxia, the most frequent of inherited ataxia in Europe, which is caused by reduced expression of the mitochondrial protein frataxin (FXN). Intwo independent cohorts of patients, we discovered that about 90% of patients were homozygous forone specific haplotype of genetic variants of the FXN3'-UTR. By a combination of computational target prediction analysis and co-transfection experiments, we showed that miRNAs, and specifically miR-124, are involved in the regulation of the FXN.We then challenged further the relationship between the miRNAs and mitochondria through questioning their localization at mitochondria. To this end, we studied miRNAs from mitochondrial and cytosolic RNA fractions isolated from the same HeLa cells. We identified a signature of 13 miRNAs specifically enriched in the mitochondrial RNA fraction that we termed ‘mitomiRs’. Through pathway-enrichement analysis, we observed a specific mitochondrial role for mitomiRs, including regulation of ATP synthesis coupled electron trasport. We also provided the evidence of Ago2 protein location inside human mitochondria at the inter-membrane space. Our work sketches miRNAs and Ago2 as a novel layer of the interplay between the nucleus and the mitochondria. We discuss whether mitochondria may be instrumental to RNA interference or a target per se. Our work paves the way to a new field of research, which may unravel therapeutic outcomes to rescue mitochondrial dysfunction.

Le virus de l'hépatite C (HCV) est responsable de maladies chroniques du foie et l'une des principales causes de développement du carcinome hépatocellulaire (HCC). Cependant, les mécanismes moléculaires qui permettent le développement d’un HCC suite à une infection chronique par le HCV restent incompris. Les microARN (miR), de petits ARNs non codants qui régulent l'expression des gènes au niveau post-transcriptionnel, sont connus pour jouer un rôle important dans l'homéostasie cellulaire du foie. De plus en plus d’études suggèrent que l'infection par le HCV induit la modification de réseaux intracellulaires impliquant les miRs hépatiques contribuant au développement des lésions du foie, y compris le HCC. En utilisant des techniques d'analyse systématiques, nous avons identifié des miRs qui modulent le cycle viral du HCV mais également des miRs modulés lors de l'infection par le HCV. Cette analyse globale des interactions entre les miRs de l'hôte et le HCV améliore les connaissances actuelles sur les interactions entre le HCV et l’hôte qui contribuent vraisemblablement à la tumorigenèse dans le foie, et ouvre des perspectives pour de potentielles nouvelles approches pour prévenir et/ou traiter le HCC chez les patients infectés par le HCV. / Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms that enable HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRs), small non coding RNAs that regulate gene expression at a post-transcriptional level have been reported to play an important role in cellular homeostasis within the liver. Increasing evidence suggests that HCV infection induces alteration of intrahepatic miR networks and that deregulation of miRs contributes to liver disease including HCC. Using high-throughput screening and RNA sequencing, we identified miRs that modulate the HCV life cycle and miRs that are modulated upon HCV infection. This comprehensive analysis of the HCV-host miR network improves the current knowledge of the HCV-host interactions that likely contribute to tumorigenesis in the liver and opens perspectives for novel potential approaches to prevent and/or treat HCC in HCV-infected patients.

Hand osteoarthritis (OA) is a degenerative joint disease that causes pain, functional limitation and negatively affects the patients' quality of life. The most severe subtype of this disease is erosive OA. Erosive hand OA is characterized by an abrupt onset, inflammation and is linked to worse outcomes than non-erosive hand OA. Current methods do not allow early diagnosis or to distinguish between patients with different forms at disease onset. This could be changed by the utilization of biomarkers in clinical practice. Biomarkers are molecules released into circulation that reflect biological processes. The main goal of this study was to analyze the levels of circulating biomarkers with the aim to differentiate patients from healthy subjects and patients with erosive OA from patients with non-erosive disease. Serum concentrations of seven biomarkers and the expression of plasma microRNAs were determined. Patients with hand OA showed altered cartilage metabolism, increased levels of adiponectin, decreased levels of clusterin and a dysregulated expression of several microRNAs in comparison to the healthy population. Patients with erosive OA had lower levels of clusterin and decreased expression of miR-151-3p than those with the non-erosive form of the disease. These findings suggest the potential...

The miR-17- 92 cluster is necessary for cell proliferation and development of the cardiovascular system. Deletion of this cluster leads to death in neonatal mice. The role of this cluster still needs to be defined following ischemia and reperfusion. Methods and Results: Adult male mice were injected with Tamoxifen- was to induce inducible cardiac-specific miR-17- 92-deficient (miR-17- 92-def: MCM:TG:miR-17- 92 flox/flox ) and wild type (WT: MCM:NTG:miR-17-92 flox/flox ) mice were subjected to 30 minutes of myocardial ischemia via left anterior descending coronary artery ligation followed by reperfusion for 24 hours. Post I/R survival (48%) and ejection fraction were reduced, while myocardial infarct size enlarged in miR-17- 92-deficient mice as compared to WT mice (survival: 71%). Necrosis (trypan blue staining) and apoptosis (TUNEL assay) both were higher in adult cardiomyocytes isolated from miR-17- 92-deficient mice as compared to WT mice subjected to simulated ischemia/reoxygenation with a concomitant reduction of mitochondrial membrane potential (JC1 staining). The electron transport chain was compromised through dysregulation of glutamate+malate as complex I substrate and malate dehydrogenase in the hearts of miR-17- 92-deficient mice compared to WT. After 4 hours of reperfusion, PTEN expression, a downstream target of miR-20A, increased, while phosphorylation of AKT reduced in the hearts of miR-17- 92-deficient mice in comparison to WT. The induced knockdown of cardiac miR-17- 92 increases myocardial I/R injury by ceasing suppression of PTEN, leading to decreased concentrations of AKT and mitochondrial dysfunction. These results suggest that innovative therapeutic strategies can focus on genetic upregulation of miR-17- 92 in patients with coronary artery disease.

The specification and modulation of cell-type specific dendritic morphologies plays a pivotal role in nervous system development, connectivity, structural plasticity, and function. Regulation of gene expression is controlled by a wide variety of cellular and molecular mechanisms, of which two major types are transcription factors (TFs) and microRNAs (miRNAs). In Drosophila, dendritic complexity of dendritic arborization (da) sensory neurons of the peripheral nervous system are known to be regulated by two transcription factors Cut and Knot, although much remains unknown about the molecular mechanisms and regulatory networks via which they regulate the final arbor shape through spatio-temporal modulation of dendritic development and dynamics. Here we use bioinformatics analysis of transcriptomic data to identify putative genomic targets of these TFs with a particular emphasis on those that effect neuronal cytoskeletal architecture. We use transcriptomic, as well as data from various genomic and protein interaction databases, to build a weighted functional gene regulatory network for Knot, to identify the biological pathways and downstream genes that this TF regulates. To corroborate bioinformatics network predictions, knot putative targets, which classify into neuronal and cytoskeletal functional groups, have been experimentally validated by in vivo genetic perturbations to elucidate their role in Knot-mediated Class IV (CIV) dendritogenesis. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, however identification of biologically-relevant target genes for this epigenetic regulatory mechanism remains a significant challenge. To address this knowledge gap, we have developed a novel R based tool, IntramiR-ExploreR, that facilitates integrated discovery of miRNA targets by incorporating target databases and novel target prediction algorithm to arrive at high confidence intragenic miRNA target predictions. We have explored the efficacy of this tool using D.melanogaster as a model organism for bioinformatics analyses and functional validation, and identified targets for 83 intragenic miRNAs. Predicted targets were validated, using in vivo genetic perturbation. Moreover, we are constructing interaction maps of intragenic miRNAs focusing on neural tissues to uncover regulatory codes via which these molecules regulate gene expression to direct cellular development.

La dysautonomie familiale (FD) est une neuropathie causée par une mutation du gène IKBKAP induisant un épissage alternatif du pré-ARNm et une déficience de la protéine IKAP/hELP1. La compréhension des mécanismes moléculaires à l'origine de la spécificité tissulaire et le développement de thérapies curatives nous ont amené à identifier une signature des microARN caractéristique de la FD reliée au facteur d'épissage neurone-spécifique NOVA1, à partir de cellules souches olfactives humaines ecto-mésenchymateuses d'individus sains ou de patients FD. De plus, nous avons identifié le protéasome 26S comme étant suractivé chez les patients et dont le blocage corrige l'épissage aberrant du pré-ARNm d'IKBKAP tout en augmentant l’expression d’IKAP/hELP1. Ainsi, l'ensemble de ce travail apporte des perspectives de recherche novatrices pour de nombreuses pathologies neurodégénératives.Nous avons mené un projet de recherche secondaire concernant l’identification de biomarqueurs sanguins pour une maladie très fréquente, la dépression. Nous avons conduit une étude translationnelle à l'aide d'un modèle animal de stress chronique (UCMS) et identifié des signatures transcriptionnelles communes entre le sang et deux régions cérébrales, le gyrus cingulaire et le gyrus dentelé. Plusieurs biomarqueurs candidats ont été validés sur des échantillons sanguins chez la Souris et l'Homme, avec une corrélation entre la variation d'expression d'ACSL1, RALGPS1 et MPP1 et l'évolution du score clinique des patients. En conclusion, ce travail identifie de nouveaux biomarqueurs potentiels de la dépression et renforce la légitimité d'analyser des tissus périphériques dans le cadre d'une pathologie mentale. / Familial dysautonomia (FD) is a neuropathy caused by a mutation in the IKBKAP gene inducing an alternative pre-mRNA splicing and a deficiency of the protein IKAP/hELP1. The understanding of molecular mechanisms underlying tissue specificity and the development of curative therapies led us to identify a particular microRNA signature in FD associated to the neuron-spécific splicing factor NOVA1, from human olfactory ecto-mesenchymal stem cells of control individuals and FD patients. Moreover, we identified the 26S proteasome as being overactived in patients and whose inhibition corrects aberrant IKBKAP pre-mRNA splicing concomitantly to an increase of IKAP/hELP1 expression level. Taken together, these results bring innovative research perspectives for many neurodegenerative diseases.We conducted a secondary project concerning the identification of blood biomarker for a very prevalent disease, major depression. We conducted a translational study using animal model of chronic stress (UCMS) and identified common transcriptional signatures between blood and two brain regions, cingulate gyrus and dentate gyrus. Several candidate biomarkers were validated as similarly dysregulated in blood of mice and men, with correlation of expression variation of ACSL1, RALGPS1 and MPP1 in relation to clinical score evolution. In conclusion, this work identifies new potential biomarkers for depression and reinforces the legitimacy to analyze peripheral tissues in the context of mental disorders.