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.