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

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Schöndorf, David C 
Ivanyuk, Dina 
Baden, Pascale 
Sanchez-Martinez, Alvaro 
De Cicco, Silvia 

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.

GBA, NAD+, Parkinson’s disease, induced pluripotent stem cells, lysosomal storage diseases, mitochondria, neurodegeneration, Animals, Autophagy, Disease Models, Animal, Dopaminergic Neurons, Drosophila melanogaster, Endoplasmic Reticulum Stress, Glucosylceramidase, Humans, Induced Pluripotent Stem Cells, Mitochondria, Mitochondrial Dynamics, Motor Activity, NAD, Neurons, Niacinamide, Parkinson Disease, Pyridinium Compounds, Unfolded Protein Response
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Elsevier BV
Medical Research Council (MC_UP_1501/1)
Medical Research Council (MC_UU_00015/6)
European Research Council (309742)