Significance of NAD anabolism profiles in neurological diseases

Neurons are post-mitotic polarized cells with a higher energy budget which is required to maintain ion gradients, axonal trafficking, firing, and synaptic transmission. The increased cell surface area resulting from the extension of the neuronal membrane and the protrusion of axoplasm from the soma also significantly amplifies neuronal energy demands. To achieve bioenergetic homeostasis, neurons have a higher metabolic rate and engage in continuous NAD production. Biosynthesis of NAD occurs via the enzymatic conversion of tryptophan, and breakdown in NAD biosynthesis leads to neuronal deterioration and the accumulation of tryptophan metabolites in affected brain regions. There exists a good body of evidence linking associations between several neurological disorders and tryptophan metabolites, aberrant expression of NAD biosynthesis enzymes, and polymorphisms in genes encoding enzymes. This review describes the involvement of NAD biosynthetic enzymes in neuropathogenesis and disease. Further, it discusses the association of CNS disorders with various polymorphisms and altered levels of tryptophan metabolites in biofluids, as well as the prognostic value of NAD-associated biomolecules in neurological diseases. Together, the review suggests that quantifying tryptophan-catabolizing enzymes and tryptophan catabolites involved in NAD biosynthesis in biofluids provides a minimally invasive means to monitor neurodegenerative and neuropsychiatric processes. This approach offers a prognostic insight into disease progression, treatment efficacy, and individualized risk assessment.