Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Nicotinamide adenine dinucleotide (NAD⁺) participates in redox reactions and NAD⁺-dependent signaling processes, which involve the cleavage of NAD⁺ coupled to posttranslational modifications of proteins or the production of second messengers. Either as a primary cause or as a secondary component of the pathogenic process, mitochondrial dysfunction and oxidative stress are prominent features of several neurodegenerative diseases. Activation of NAD⁺-dependent signaling pathways has a major effect in the capacity of the cell to modulate mitochondrial function and counteract the deleterious effects of increased oxidative stress. Recent Advances: Progress in the understanding of the biological functions and compartmentalization of NAD⁺-synthesizing and NAD⁺-consuming enzymes have led to the emergence of NAD⁺ metabolism as a major therapeutic target for age-related diseases.

Three distinct families of enzymes consume NAD⁺ as substrate: poly(ADP-ribose) polymerases (PARPs), ADP-ribosyl cyclases (CD38/CD157) and sirtuins. Two main strategies to increase NAD⁺ availability have arisen. These strategies are based on the utilization of NAD⁺ intermediates/precursors or the inhibition of the NAD⁺-consuming enzymes, PARPs and CD38. An increase in endogenous sirtuin activity seems to mediate the protective effect that enhancing NAD⁺ availability confers in several models of neurodegeneration and age-related diseases.

A growing body of evidence suggests the beneficial role of enhancing NAD⁺ availability in models of neurodegeneration. The challenge ahead is to establish the value and safety of the long-term use of these strategies for the treatment of neurodegenerative diseases. Antioxid. Redox Signal. 28, 1652-1668.