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.