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, ARNt et 2 ARNr. Le reste des protéines, codé par le génome nucléaire, est importé après traduction dans le cytosol

, Parmi les protéines importées figurent les aminoacyl-ARNt synthétases (aaRS), la présence d'une séquence N-terminale (MTS pour "mitochondrial targeting sequence"), clivée après importation, 2007.

&. Aujourd and . Hui, Des mutations dans le gène RARS2, qui code pour l'ArgRS mt, sont corrélées à une maladie neurodéveloppementale sévère, PCH6 (pour "Pontocerebellar Hypoplasia type 6"). L'implication de ces deux protéines dans la traduction mitochondriale pourrait conduire à l'idée que une fois mutées, leurs dysfonctionnements produisent des conséquences similaires, toutes les aaRS mt sont impliquées dans des maladies aux conséquences souvent sévères

, Des mutations dans la ArgRS sont liées à une hypoplasie Pontocérébelleuse (PCH6), une pathologie neurodéveloppementale sévère. Le travail de cette thèse s'articule autour de 3 axes : (I) L'analyse des phénotypes cliniques des pathologies liées aux mutations dans les aaRS mt, (II) La caractérisation des propriétés cellulaires de l'ArgRS mt, et (III) L'étude de l'impact de mutations « pathologiques » sur diverses propriétés de l'ArgRS mt. Combinés avec les travaux précédents, les résultats obtenus sont une contribution importante à l, Le travail de cette thèse s'articule autour de 3 axes : (I) L'analyse des phénotypes cliniques des pathologies liées aux mutations dans les aaRS mt

, Mots clés: traduction mitochondriale, mitochondrial aminoacyl-ARNt synthétase, aminoacylation, organisation sous mitochondriale, pathologies liées aux mutations

, Mutations in their nuclear genes are correlated with pathologies with a broad spectrum of clinical phenotypes, but with so far no clear explanations about the underlying molecular mechanism(s). The aim of this PhD work follows the long-standing efforts of the host laboratory but expand the interest and knowledge to an unexplored system: the human mitochondrial arginyl-tRNA synthetase (mt-ArgRS). Mutations in the mt-ArgRS lead to Pontocebellar hypoplasia type 6, a severe neuro-developmental pathology. I thus contributed to i) comprehensively analyze the clinical data reported in pathologies related to mutations on mt-aaRSs, resulting in a categorization according to the affected anatomical system; ii) decipher some cellular properties of the mtArgRS; and iii) investigate to impact of disease-associated mutations on mt-aaRSs properties, Abstract Human mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are housekeeping enzymes involved in the mitochondrial translation

, Keywords: mitochondrial translation, mt-aaRSs, aminoacylation, sub-mitochondrial localization, pathology-related mutations