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

• Published in: Cell reports (Cambridge) Vol. 23; no. 10; pp. 2976 - 2988
• Main Authors: Schöndorf, David C., Ivanyuk, Dina, Baden, Pascale, Sanchez-Martinez, Alvaro, De Cicco, Silvia, Yu, Cong, Giunta, Ivana, Schwarz, Lukas K., Di Napoli, Gabriele, Panagiotakopoulou, Vasiliki, Nestel, Sigrun, Keatinge, Marcus, Pruszak, Jan, Bandmann, Oliver, Heimrich, Bernd, Gasser, Thomas, Whitworth, Alexander J., Deleidi, Michela
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.06.2018
• Subjects: Animals; Autophagy; Disease Models, Animal; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Drosophila melanogaster - physiology; Endoplasmic Reticulum Stress; GBA; Glucosylceramidase - metabolism; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - pathology; lysosomal storage diseases; mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria - ultrastructure; Mitochondrial Dynamics; Motor Activity; NAD; NAD - metabolism; neurodegeneration; Neurons - metabolism; Neurons - pathology; Niacinamide - analogs & derivatives; Niacinamide - metabolism; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson’s disease; Pyridinium Compounds; Unfolded Protein Response; NAD; lysosomal storage diseases; mitochondria; GBA; neurodegeneration; induced pluripotent stem cells; Parkinson’s disease
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.05.009

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.