DISC1, a strong genetic candidate for psychiatric illness, is a molecular scaffold residing in multiple subcellular compartments, where it regulates the function of interacting proteins with key roles in neurodevelopment and plasticity. Both common and rare DISC1 missense variants are associated with risk of mental illness and/or brain abnormalities in healthy carriers, but the underlying mechanisms are unclear. In this thesis, I initially examine the effect of a panel of common and rare single amino acid substitutions on DISC1 subcellular targeting, establishing that the rare mutation R37W and the common variant L607F disrupt DISC1 nuclear targeting in a dominant-negative fashion. This finding predicts that DISC1 nuclear expression is severely impaired in 37W and 607F carriers. In addition, I show that the L607F substitution results in aberrant cytoplasmic and cytoskeletal distribution of DISC1. In the nucleus, DISC1 interacts with the transcription factor ATF4, which is involved in the regulation of cellular stress responses and memory consolidation. Here I show that at basal cAMP levels, wild-type DISC1 strongly inhibits the transcriptional activity of ATF4, and this effect is ablated by 37W and 607F, most likely as a consequence of their defective nuclear targeting. 607F additionally reduces DISC1/ATF4 interaction, which likely contributes to its weakened inhibitory effect. I also demonstrate that DISC1 modulates transcriptional responses to endoplasmic reticulum stress, and that this modulatory effect is also ablated by 37W and 607F. By providing evidence that single amino acid substitutions of DISC1 associated with psychiatric illness impair its regulatory function on ATF4-dependent transcription, I highlight a potential mechanism by which these protein variants may impact on molecular pathways underlying cognition and stress responses, two processes of direct relevance to psychiatric disease.

L’acide phosphatidique (PA) est un lipide simple qui peut exister sous différentes formes. A partir des sondes que j’ai préparé en se basant sur des domaines de liaison au PA : PDE4A1, Spo20p, et OpiQ2, j’ai pu étudier la localisation subcellulaire du PA dans les cellules PC12 et les macrophages RAW264.7. Ces sondes lient différents formes de PA dans les membranes de différents compartiments subcellulaires. De plus, j’ai pu montrer qu’il y a une néosynthèse de PA et de certaines espèces de PA mono- ou bi-insaturé à la membrane plasmique lors de la stimulation de l’exocytose. Nous avons ainsi observé que la PLD1 semble être la source principale de PA dans les glandes surrénales. D’autre part, mes travaux indiquent une augmentation du niveau global de PA à la membrane plasmique et une diminution importante du PA au niveau du RE dans les macrophages après stimulation de la phagocytose frustrée. Ce qui pourrait ainsi valider le concept d’une fusion d’une partie de la membrane du RE avec la membrane plasmique lors de la phagocytose. / The phosphatidic acid (PA) is a simple lipid which may exist in various forms. I have generated probes based on PA binding domains: PDE4A1, Spo20p and OpiQ2 to study the subcellular localization of PA in PC12 cells and RAW264.7 macrophages. These probes bind different form of PA in different subcellular compartments. In addition, I show that PA and certain species mono- or bi-unsaturated of PA are synthesized at the plasma membrane upon stimulation of exocytosis. We observed that the PLD1 seems to be the main source of PA in the adrenal glands. On the other hand, my research indicates an increase in the level of PA at the plasma membrane and a significant decrease in the ER in macrophages after stimulation of phagocytosis frustrated. Thus these results could validate the concept of a fusion of a portion of the ER membrane with the plasma membrane during phagocytosis.