The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease

While mitochondrial dysfunction is emerging as key in Parkinson’s disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD. Our findings suggest NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases. [Display omitted] •NAD+ metabolism and mitochondrial function are altered in GBA-PD neurons•Human iPSC-derived neurons are responsive to NAD+ precursors•Nicotinamide riboside improves mitochondrial function in GBA-PD iPSC neurons•Nicotinamide riboside rescues neuronal loss and motor deficits in GBA-PD flies Mitochondrial damage is a key feature in Parkinson’s disease. Schöndorf et al. demonstrate that nicotinamide riboside, an NAD+ precursor, boosts mitochondrial function in neurons derived from Parkinson’s disease patient stem cells and is neuroprotective in Parkinson’s disease fly models. These findings support use of NAD+ precursors in Parkinson’s and other neurodegenerative diseases.