Neurons need to be maintained to persist throughout adulthood for proper brain function. However neuronal activity, injury and aging exert physical stress on the nervous system, which compromise nervous system function. Healthy neurons are able to maintain their integrity throughout the lifespan of the animal, suggesting the existence of a maintenance mechanism that allows neurons to sustain or even repair damage. A forward genetic screening in Drosophila identified mutations in a gene called nmnat that cause a rapid and severe neurodegeneration immediately post neuronal differentiation and development. NMNAT protein was required to maintain neuronal integrity in an activity-dependent manner. When probing for the exact role of NMNAT in neuronal maintenance, a novel stress responsive chaperone function was identified, in addition to its essential housekeeping NAD synthase role. In this work, the mechanism of NMNAT-mediated neuroprotection is investigated. First, the transcriptional regulation of Drosophila NMNAT during acute stress is analyzed. Here, both stress transcription factors heat shock factor (HSF) and hypoxia inducible factor alpha (HIF1-α) have been shown to upregulate NMNAT during stress through a heat shock element in the nmnat promoter. In addition, the role of NMNAT for stress tolerance in Drosophila is revealed. Second, to elucidate the neuroprotective capacity of NMNAT in neurodegenerative disease, mouse models of tauopathy have been used. In the P301L Tau-transgenic mouse model, the levels of endogenous NMNAT2 have been studied at various ages to link a reduction in NMNAT2 as a precursor for neurodegeneration. The underlying mechanism of NMNAT2 downregulation is further studied in this model. Third, using Drosophila model of Tauopathy, the protective capacity of both wild type and enzyme-inactive NMNAT in ameliorating the pathological and behavioral impairments from Tau-induced neurodegeneration were studied extensively. The possible protective mechanism of NMNAT is uncovered by identifying novel interactions of NMNAT with hyperphosphorylated and ubiquitinated Tau in regulating the levels of toxic Tau species. Finally, this study also identified endogenous proteins that NMNAT interacts with to provide insight into a neuroprotective chaperone role of NMNAT. Together, these studies improve our understanding of the mechanisms of neuronal maintenance, by providing a comprehensive investigation of the stress-responsive regulation of NMNAT in both Drosophila and mammalian models, and its role as a chaperone both in protein foldopathies and in healthy neurons.

Tout au long de la vie d’un organisme, l’architecture du système nerveux est mise à l’épreuve par des processus de maturation, de croissance, de stress mécaniques et de vieillissement. Bien que certaines molécules de maintenance de l’organisation des ganglions et fascicules neuronaux aient été identifiés chez le nématode C. elegans, les mécanismes assurant la protection à long terme de l’architecture du système nerveux restent mal compris. Chez les mutants de maintenance neuronale sax-7/L1CAM, certaines structures neuronales se développent initialement normalement, mais se désorganisent avec le temps. Un criblage génétique effectué au laboratoire a indiqué l’implication du gène mig-6/Papiline dans la maintenance neuronale: la perte de fonction de mig-6 supprime la désorganisation neuronale progressive des mutants sax-7. De plus, l’organisation neuronale des mutants mig-6 est mieux préservée dans un contexte de stress mécanique que chez le type sauvage. Un équilibre entre l'adhésion cellulaire et la flexibilité du milieu semble donc clé. Par ailleurs, les cellules gliales sont en relation étroite avec les neurones, mais leur implication dans la maintenance neuronale reste inexplorée. Ainsi, lors de ces travaux, la question principale est d’étudier la contribution de la matrice extracellulaire et de cellules gliales dans un contexte de maintenance de l’architecture du système nerveux chez C. elegans. Les résultats révèlent que MIG-6/Papiline régule l’état de la matrice extracellulaire en modifiant l’organisation du collagène IV, un composant abondant et conservé des membranes basales. Cette modification du collagène IV semble compenser les défauts d’adhésion cellulaire présents chez les mutants de maintenance sax-7/L1CAM et contrer un déplacement des ganglions neuronaux lors d’un stress mécanique accru. L’exploration de cellules gliales en contexte de maintenance neuronale a mis en évidence certains défauts des mutants de maintenance sax-7/L1CAM. Comprendre les principes généraux du maintien de l'architecture et de la connectivité neuronale pourrait aider à identifier des facteurs clés influençant l'apparition et la progression de neuropathologies. / Throughout life, the architecture of the nervous system is challenged by processes of maturation, growth, mechanical stress and aging. Although neuronal maintenance mechanisms of ganglia and fascicles organization involving conserved factors have been identified in the nematode C. elegans, little is known about processes that aim for the long-term protection of the nervous system architecture. In sax-7/L1CAM neuronal maintenance mutants, some neuronal ganglia and fascicles initially develop normally, but become disorganized over time. A genetic screen performed in the laboratory indicated the involvement of mig-6/Papilin in neuronal maintenance: loss of mig-6 function suppresses progressive neuronal disorganization in sax-7 mutants. Moreover, the neuronal organization of mig-6 mutants is better preserved under mechanical stress than in the wild-type strain. A balance between the adhesion of neurons to their environment and the flexibility of the surrounding extracellular matrix thus seems of importance. Furthermore, glial cells are closely related to neurons, but their involvement in the maintenance of the organization of neuronal structures remains unexplored. The main question of this work is to study the contribution of the extracellular matrix and of two types of glial cells in the context of maintenance of the nervous system architecture in C. elegans. Our results reveal that MIG-6/Papilin regulates the state of the extracellular matrix by altering the organization of collagen IV, an abundant and conserved component of basement membranes, thus compensating for cell adhesion defects in sax-7/L1CAM maintenance mutants and counteracting a neural ganglia displacement upon increased mechanical stress. Our exploration of glial cells in the context of neuronal maintenance also revealed defects in sax-7/L1CAM maintenance mutants. Understanding the general principles of maintenance of neuronal architecture and connectivity could help identify key factors influencing the onset and progression of neuropathologies.