Neurodegeneration can be triggered by a variety of genetic, epigenetic, and environmental factors.Healthy neurons are able to maintain their integrity throughout the life of an organism, suggesting the existence of a maintenance mechanism that allows neurons to sustain, mitigate or even repair damage.Recently, we have identified a neuronal maintenance factor NMNAT in a forward genetic screen in Drosophila.Loss of nmnat causes rapid and severe neurodegeneration, whereas over-expression of NMNAT protein offers protection against neurodegeneration.These findings suggest that normal level of NMNAT maintains neuronal homeostasis, and increased level offers protection.Our studies found that in addition to its NAD synthesis activity, NMNAT has a chaperone function that is involved in regulating protein misfolding and degradation.NMNAT is up-regulated under stress, reduces protein aggregation, and thus protects neurons from degenerative conditions.Importantly the function of NMNAT is conserved from yeast to human.We demonstrated the neuroprotective activity of NMNAT in both Drosophila and mammalian models of Tauopathy where NMNAT reduces protein aggregation-induced neurotoxicity.Our research in both Drosophila and mammalian model systems discovered an endogenous neuroprotective program.Characterization of this program and its regulatory mechanisms will help the design of neuroprotective therapies for neurodegenerative disorders.