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

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. 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. 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. 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. . 39, 1150-1166.