Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson’s disease
Open accessAbstract
The co-enzyme nicotinamide adenine dinucleotide (NAD + ) is an essential co-factor for cellular energy generation in mitochondria as well as for DNA repair mechanisms in the cell nucleus involving NAD + -consuming poly (ADP-ribose) polymerases (PARPs). Mitochondrial function is compromised in animal models of Parkinson’s disease (PD) associated with PARKIN mutations. Here, we uncovered alterations in NAD + salvage metabolism in Drosophila parkin mutants. We show that a dietary supplementation with the NAD + precursor nicotinamide rescues mitochondrial function and is neuroprotective. Further, by mutating Parp in parkin mutants, we show that this increases levels of NAD + and its salvage metabolites. This also rescues mitochondrial function and suppresses dopaminergic neurodegeneration. We conclude that strategies to enhance NAD + levels by administration of dietary precursors or the inhibition of NAD + -dependent enzymes, such as PARP, that compete with mitochondria for NAD + could be used to delay neuronal death associated with mitochondrial dysfunction.
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Supplementation with the NAD+ precursor NAM rescues mitochondrial defects and behavioural impairments in Alzheimer's disease models but suppresses dopaminergic neurodegeneration in a Drosophila Parkinson's disease model.
“Supplementation with the NAD+ precursor NAM rescues mitochondrial defects and behavioural impairments in AD models410 but suppresses dopaminergic neurodegeneration in a Drosophila PD model.411”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [411]
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“355,356 Other approaches may limit PAR-mediated PS of α -synuclein, which is one of the most upstream components of the pathway.”
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DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease
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NAD+ Metabolism and Diseases with Motor Dysfunction
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“Moreover, manipulation of d Parp or d Parg gene expression levels led to altered phenotypes in fl y models of neurodegenerative diseases such as Parkinson ’ s disease 42,43 , Alzheimer ’ s disease 44 , and amyotrophic lateral sclerosis 45 .”
Progresses in both basic research and clinical trials of NAD+ in Parkinson’s disease
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Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain
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Cancer enzyme affects Parkinson's disease
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Ageing, Drosophila melanogaster and Epigenetics
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“In addition, PARP also involves in other ageing-related mechanism like DNA repair (83), biogenesis of ribosome (84) and also cell death (85).”
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“Inhibition of PARP1, by gene mutation or drug inhibition, suppressed dopaminergic neurodegeneration in AIMP2 overexpressing mice and in Drosophila parkin mutants [43,44].”
Drosophila melanogaster as a Model for Studying the Epigenetic Basis of Aging
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Molecular evolutionary patterns of NAD+/Sirtuin aging signaling pathway across taxa
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“Inhibition of PARP has resulted in protection against mitochondrial dysfunction and neurodegeneration in Parkinson fruit fly model [52].”
Nicotinamide Adenine Dinucleotide (NAD + )-Dependent Signaling in Neurological Disorders
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“Likewise, PARP mutations are protective in Drosophila models of PD with Pink1 mutations (Lehmann et al., 2017; Lehmann et al., 2016), while PARP inhibition is protective in the mutant a -synuclein A53T model (Mao et al., 2020), suggesting that PARP1 inhibitors may be beneficial in the treatment of…”
Intracellular and Intercellular Signalling Mechanisms following DNA Damage Are Modulated By PINK1
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Preparation of Viable Human Neurites for Neurobiological and Neurodegeneration Studies
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“They also reflected upon the fact that an increase in NAD þ levels through dietary supplementation (Vitamin B3 in the form of NAM) could lead to an improvedmitochondrial functioning and possibly have a neuroprotective effect in Parkin mutants (Lehmann et al., 2016).”
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Approaches for Identifying Novel Targets in Precision Medicine: Lessons from DNA Repair
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“NAD + supplementation was found to be protective against several models of neurodegenerative diseases, including AD, PD, and ALS [21, 71, 72].”
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“Studies have shown that NAD + levels in neurons decrease after axonal injury or neurodegenerative diseases [17,18], suggesting that NAD + plays a key role in the underlying process of axonal degeneration.”
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Absence of pretaporter restrains features of the parkin phenotype in Drosophila
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Vitamin B3 salvage and NAD\(^+\) metabolism in skeletal muscle
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A Drosophila model of prion disease and its metabolic changes in the brain
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“Consistent with established PD 21–23 and PrDs models, 24,25 we con - ducted all experiments exclusively on adult male flies in this study.”
Targeting Poly (ADP‐Ribose) Polymerase‐1 for the Treatment of Neurodegenerative Diseases
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“Inhibiting NAD+- dependent enzymes, such as PAR1, using nicotinamide as an inhibitor to compete with mitochondria for NAD+ could delay neuronal death associated with mitochondrial dysfunction (Jung et al. 2022; Lehmann et al. 2016).”
Co-activation and signal crosstalk between parthanatos and mitophagy in light-induced retinal injury
Li, Y. L., Zhang, S., Fan, B., & Li, G.-Y. (2026) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2026.113475
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“In mouse models exhibiting DNA repair deficiencies, PARP inhibition has been shown to prevent NAD + depletion and premature aging, while increasing NAD + levels and enhancing mitochondrial health and function [11].”
Lautrup, S., Cao, S., Long, X., Liu, B. H. M., Escobar-Doncel, B., Ferrante, A., Frank, J., Schmauck‐Medina, T., Leung, G. H. D., Liang, K. X., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71680
- Authors
- Lehmann, S., Costa, A. C., Celardo, I., Loh, S. H. Y., & Martins, L. M.
- Affiliations
- MRC Toxicology Unit (GB)
- Corresponding author
- Loh, S H Y
- Martins, L M
- Venue
- Cell Death & Disease
- Published
- 2016-03-31
- Volume
- 7
- Issue
- 3
- Pages
- e2166-e2166
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4823968
- OpenAlex
- W2322530366
- Cited by
- 69
- References
- 40
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 12 · 2016: 2
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Funders
- Emory University
- 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
- poly(ADP-ribose) polymerase, parkin mutations, Parkinson's disease, nicotinamide, mitochondrial dysfunction, dopaminergic neuron loss, neuroprotection, Drosophila, NAD+ precursor supplementation
- MeSH terms
- Animals, Brain, Disease Models, Animal, Drosophila, Genotype, Longevity, Male, Mitochondria, NAD, Niacinamide, Parkinson Disease, Poly(ADP-ribose) Polymerases, Blotting, Western, Mutagenesis, Dietary Supplements, Drosophila Proteins, Ubiquitin-Protein Ligases, Membrane Potential, Mitochondrial, Dopaminergic Neurons
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