Nicotinamide Adenine Dinucleotide (NAD ⁺ )-Dependent Signaling in Neurological Disorders

Significance: Nicotinamide adenine dinucleotide (NAD + ) participates in redox reactions and NAD + -dependent signaling processes, which couples the enzymatic degradation of NAD + to posttranslational modifications of proteins or the production of second messengers. Cellular NAD + levels are dynamically controlled by synthesis and degradation, and dysregulation of this balance has been associated with acute and chronic neuronal dysfunction. Recent Advances: A decline in NAD + has been observed during normal aging and since aging is the primary risk factor for many neurological disorders, NAD + metabolism has become a promising therapeutic target and prolific research field in recent years. Critical Issues: In many neurological disorders, either as a primary feature or as consequence of the pathological process, neuronal damage is accompanied by dysregulated mitochondrial homeostasis, oxidative stress, or metabolic reprogramming. Modulating NAD + availability appears to have a protective effect against such changes observed in acute neuronal damage and age-related neurological disorders. Such beneficial effects could be, at least in part, due to the activation of NAD + -dependent signaling processes. Future Directions: While in many instances the protective effect has been ascribed to the activation of sirtuins, approaches that directly test the role of sirtuins or that target the NAD + pool in a cell-type-specific manner may be able to provide further mechanistic insight. Likewise, these approaches may afford greater efficacy to strategies aimed at harnessing the therapeutic potential of NAD + -dependent signaling in neurological disorders. Antioxid. Redox Signal . 39, 1150–1166.