Rôle des modulateurs de la longévité et du métabolisme énergétique sur la réponse cellulaire à la protéine PABPN1 mutée (identification de pistes thérapeutiques pour le traitement de la dystrophie musculaire oculopharyngée)

La dystrophie musculaire oculopharyngée (DMOP) est une maladie causée par des polyalanines mutées dans PABPN1 (PolyAdenosine Binding Protein Nuclear 1), mais dont les mécanismes restent inconnus. Afin d étudier la toxicité de PABPN1 mutée, nous l avons exprimée dans les muscles du nématode Caenorhabditis elegans et dans des cellules mammifères COS-7. Nous avons observé que la protéine PABPN1 mutée produit une dégénérescence cellulaire et altère la mobilité des nématodes. Nous avons montré qu il existe des anomalies de l acétylation des histones qui sont compensées par un inhibiteur général des histones désacétylases et que l inhibition de SIR2, une désacétylase de classe III, protège la cellule. De plus, les facteurs de transcription FOXO et les régulateurs du métabolisme énergétique comme l AMPK, participent à ces effets, leur inactivation étant protectrice. En conclusion, nos résultats indiquent que les modulateurs de la longévité et du métabolisme énergétique modulent les effets cytotoxiques des polyalanines mutées dans la protéine PABPN1 et suggèrent de nouvelles pistes thérapeutiques pour la DMOP.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Plasma thermal conversion of bio-oil for hydrogen production

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Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson’s correlation coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10−5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD

The GLAM Airborne Campaign across the Mediterranean Basin

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MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs at night, which is often accompanied by unpleasant sensations. A recent genomewide association study identified an association between RLS and intronic markers from the MEIS1 gene. Comparative genomic analysis indicates that MEIS1 is the only gene encompassed in this evolutionarily conserved chromosomal segment, i.e. a conservation synteny block, from mammals to fish. We carried out a series of experiments to delineate the role of MEIS1 in RLS pathogenesis and the underlying genetic mechanism. We sequenced all 13 MEIS1 exons and their splice junctions in 285 RLS probands with confirmed clinical diagnosis and did not identify any causative coding or exon–intron junction mutations. We found no evidence of structural variation or disease-associated haplotype differential splicing. However, sequencing of conserved regions of MEIS1 introns 8 and 9 identified a novel single nucleotide polymorphism (C13B_2) significantly associated with RLS (allelic association, P = 1.81E−07). We detected a significant decrease in MEIS1 mRNA expression by quantitative real-time polymerase chain reaction in lymphoblastoid cell lines (LCLs) and brain tissues from RLS patients homozygous for the intronic RLS risk haplotype, compared with those homozygous for the non-risk haplotype. Finally, we found significantly decreased MEIS1 protein levels in the same batch of LCLs and brain tissues from the homozygous carriers of the risk haplotype, compared with the homozygous non-carriers. Therefore, these data suggest that reduced expression of the MEIS1 gene, possibly through intronic cis-regulatory element(s), predisposes to RLS