Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration.

SIGNIFICANCE

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.

CRITICAL ISSUES

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.

FUTURE DIRECTIONS

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.