TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well understood. We postulate that the aggregation process plays a major role in pathogenesis, and we hypothesize that oligonucleotide ligands of TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation of this aggregation-prone protein. Using recombinant TDP-43 we were able to examine the extent to which various oligonucleotide molecules affects its aggregation in vitro. We have found that certain natural sequence and de novo designed oligonucleotides bind TDP-43 and prevent its natural tendency to aggregate. The clinical and therapeutic implications of these findings are discussed.

TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well understood. We postulate that the aggregation process plays a major role in pathogenesis, and we hypothesize that oligonucleotide ligands of TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation of this aggregation-prone protein. Using recombinant TDP-43 we were able to examine the extent to which various oligonucleotide molecules affects its aggregation in vitro. We have found that certain natural sequence and de novo designed oligonucleotides bind TDP-43 and prevent its natural tendency to aggregate. The clinical and therapeutic implications of these findings are discussed.

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Cette thèse s'intéresse au problème de préparation et de stabilisation de systèmes quantiques. Nous considérons des modèles correspondant à des expériences actuelles en électrodynamique quantique en cavité, circuits Josephson, et de contrôle quantique cohérent par laser femtoseconde. Nous posons les problèmes dans le contexte de la théorie du contrôle et nous proposons des lois de commande qui préparent ou stabilisent des états cibles. En particulier, nous nous intéressons à des états cibles qui n'ont pas d'analogue classique: des états superpositions et intriqués. De plus, nous proposons une commande pour la stabilisation d'un sous-espace de l'espace des états, contribuant ainsi au domaine de la correction d'erreur quantique. Ces résultats ont été obtenu en étroite collaboration avec des expérimentateurs. Des mesures expérimentales préliminaires sont en bon accord avec certaines prédictions théoriques de cette thèse. / This thesis tackles the problem of preparing and stabilizing highly non classical states of quantum systems. We consider specific models based on current experiments in cavity quantum electrodynamics, Josephson circuits and ultra-fast coherent quantum control. The problem is posed in the framework of control theory where we search for a control law which prepares or stabilizes a desired target state.Of particular interest to us are target states with no classical analog: superposition and entangled states. More generally, we propose a scheme for the stabilization of a manifold of quantum states, thus introducing some new ideas for autonomous quantum error correction in a cavity. Close collaborations with experimentalists helped us in the design of control protocols which are readily employable in the laboratory. Experimental demonstrations are currently being implemented and preliminary measurements are in good agreement with the theory introduced in this thesis.