The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease.
Schöndorf, David C
De Cicco, Silvia
Schwarz, Lukas K
Di Napoli, Gabriele
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Schöndorf, D. C., Ivanyuk, D., Baden, P., Sanchez-Martinez, A., De Cicco, S., Yu, C., Giunta, I., et al. (2018). The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease.. Cell reports, 23 (10), 2976-2988. https://doi.org/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. 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.
Neurons, Mitochondria, Animals, Humans, Drosophila melanogaster, Parkinson Disease, Disease Models, Animal, Niacinamide, NAD, Glucosylceramidase, Motor Activity, Autophagy, Unfolded Protein Response, Induced Pluripotent Stem Cells, Endoplasmic Reticulum Stress, Dopaminergic Neurons, Mitochondrial Dynamics
European Commission FP7 ERC Starting Independent Researcher Grant (SIRG) (309742)
External DOI: https://doi.org/10.1016/j.celrep.2018.05.009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279792
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/