Nicotinamide mononucleotide treatment increases NAD+ levels in an iPSC Model of Parkinson’s Disease

Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra that leads to severe motor and non-motor deficits. Although the underlying mechanisms of dopaminergic neuron loss is not entirely clear, increasing evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. Recently, we found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels, an essential cofactor in mitochondrial function and cellular metabolism. In addition, we found that sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival, displayed decreased activity in PD dopaminergic neurons, thereby suggesting a potential mechanism for dopaminergic loss in PD. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with an NAD+ precursor could increase NAD+ levels and improve sirtuin activity.