The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson's disease
Open accessAbstract
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.
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Dopaminergic neurons derived from iPSCs expressing mutant GBA exhibit a reduced cytosolic NAD+/NADH ratio, although no significant change in total cellular NAD+ was seen.
“Dopaminergic neurons derived from iPSCs expressing mutant GBA exhibit a reduced cytosolic NAD+/NADH ratio, although no significant change of total cellular NAD+ was seen (Schöndorf et al., 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Schöndorf et al., 2018
P7C3 was shown to be neuroprotective in mouse models of Parkinson disease, Alzheimer disease and ALS.
“P7C3 was shown to be neuroprotective in mouse models of Parkinson disease137, Alzheimer disease157 and ALS158.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [137]
NAD+ depletion is reported in several models of accelerated ageing that exhibit neurodegeneration, as well as in neurodegenerative diseases including Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis.
“NAD+ depletion is reported in several models of accelerated ageing which exhibit neurodegeneration33,134,135, as well as in neuro-degenerative diseases, including Alzheimer disease136, Parkinson disease137,138 and amyotrophic lateral sclerosis (ALS)139.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [137]
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- Authors
- Schöndorf, D. C., Ivanyuk, D., Baden, P., Sanchez-Martinez, A., De Cicco, S., Yu, C., Giunta, I., Schwarz, L. K., Di Napoli, G., Panagiotakopoulou, V., Nestel, S., Keatinge, M., Pruszak, J., Bandmann, O., Heimrich, B., Gasser, T., Whitworth, A. J., & Deleidi, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- University of Cambridge (GB)
- University of Freiburg (DE)
- University of Sheffield (GB)
- Corresponding author
- Deleidi, Michela
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 23
- Issue
- 10
- Pages
- 2976-2988
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2805234895
- Cited by
- 337
- References
- 39
- Citations by year
- 2026: 33 · 2025: 32 · 2024: 45 · 2023: 50 · 2022: 55 · 2021: 51 · 2020: 44 · 2019: 23 · 2018: 4
- FWCI
- 20.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- European Research Council (309742)
- Medical University of South Carolina
- Deutsche Forschungsgemeinschaft (DE 2157/2-1)
- Helmholtz Association (VH-NG-1123)
- Marie Curie (CIG304108)
- National Institutes of Health (C06 RR018823)
- Medical Research Council (MC-A070-5PSB0)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, nicotinamide riboside, NAD+ precursors, mitochondrial dysfunction, visfatin, dopaminergic neuron loss, neuroprotection, iPSC-derived neurons, Drosophila model, mitochondrial biogenesis, NAD+ metabolism
- MeSH terms
- Animals, Autophagy, Disease Models, Animal, Drosophila melanogaster, Glucosylceramidase, Humans, Mitochondria, Motor Activity, NAD, Neurons, Niacinamide, Parkinson Disease, Pyridinium Compounds, Unfolded Protein Response, Induced Pluripotent Stem Cells, Dopaminergic Neurons, Endoplasmic Reticulum Stress, Mitochondrial Dynamics
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