NAD METABOLISM IN THE PATHOPHYSIOLOGY AND THERAPY OF PARKINSON'S DISEASE
Abstract
This paper explores the rapidly increasing incidence of Parkinson's disease (PD) and the limitations of current dopamine-based therapies, which only address symptoms rather than underlying causes. This has spurred research into novel treatment approaches rooted in the disease's pathophysiology. A key pathological hallmark of PD is mitochondrial dysfunction, particularly affecting complex I, a critical component of cellular energy metabolism. This discovery has directed investigations toward individual elements of mitochondrial pathways, including the NAD+/NADH redox balance. Studies indicate reduced NAD+ levels in the brains of individuals with PD, prompting research into the therapeutic effects of NAD+ supplementation. This review summarizes recent scientific findings on how augmenting NAD+ and its derivatives may influence Parkinson's disease. It discusses the impact of NAD+ precursor supplementation on mitochondrial function and NAD+ levels in neurons carrying the GBA mutation. The paper also covers defects in PINK1 expression, their link to PD development, and the potential role of Nicotinamide (vitamin B3) in this context. Additionally, it assesses the safety of oral NAD+ precursor supplementation and its effects on brain NAD+ levels and metabolism in PD patients. A deeper understanding of PD pathophysiology and continued research into raising NAD+ levels are vital for developing novel therapeutic strategies. Modulating NAD+ holds significant promise as a supportive or disease-modifying therapy for this neurodegenerative condition.
References
Dorsey ER, Sherer T, Okun MS, et al.: The Emerging Evidence of the Parkinson Pandemic. J Parkinsons Dis. 2018, 8:3-8. 10.3233/JPD-181474
Bloem BR, Okun MS, Klein C. : Parkinson’s disease.. The Lancet. 2021, 397:2284-2303. 10.1016/S0140-6736(21)00218-X
Armstrong MJ, Okun MS.: Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2021, 323:548-560. 10.1001/jama.2019.22360
Simon DK, Tanner CM, Brundin P.: Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology. Clin Geriatr Med. 2020, 36:1-12. 10.1016/j.cger.2019.08.002
Schapira AH, Cooper JM, Dexter D, et al.: Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem. 1990, 54:823-7. 10.1111/j.1471-4159.1990.tb02325.x
Subramaniam SR, Chesselet MF. : Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013, 106:17-32. 10.1016/j.pneurobio.2013.04.004
Zhu J, Vinothkumar KR, Hirst J: Structure of mammalian respiratory complex I. Nature. 2016, 536(7616):354-358. 10.1038/nature19095
Li JL, Lin TY, Chen PL, et al.: Mitochondrial Function and Parkinson’s Disease: From the Perspective of the Electron Transport Chain. Front Mol Neurosci. 2021, 9:797833-10. 10.3389/fnmol.2021.797833
Johnson ME, Bobrovskaya L: An update on the rotenone models of Parkinson's disease: their ability to reproduce the features of clinical disease and model gene-environment interactions. Neurotoxicology. 2015, 46:101-16. 10.1016/j.neuro.2014.12.002
Anderson AJ, Jackson TD, Stroud DA, et al.: Mitochondria-hubs for regulating cellular biochemistry: emerging concepts and networks.. Open Biol. 2019, 9(8):190126. 10.1098/rsob.190126
Sena LA, Chandel NS: Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012, 48(2):158-67. 10.1016/j.molcel.2012.09.025
Covarrubias AJ, Perrone R, Grozio A, et al.: NAD+ metabolism and its roles in cellular processes during ageing.. Nat Rev Mol Cell Biol. 2021, 22(2):119-141. 10.1038/s41580-020-00313-x
Hikosaka K, Yaku K, Okabe K, et al.: Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. Nutritional neuroscience. 2021, 24:371-383. 10.1080/1028415X.2019.1637504
Lautrup S, Sinclair DA, Mattson MP, et al.: NAD+ in Brain Aging and Neurodegenerative Disorders. Cell metabolism. 2019, 30:630-655. 10.1016/j.cmet.2019.09.001
Jia F, Fellner A, Kumar KR. : Monogenic Parkinson's Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing. Genes. 2022, 13:471-10. 10.3390/genes13030471
Kuo SH, Tasset I, Cheng MM, et al.: Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy. Science advances. 2022, 8:6393. 10.1126/sciadv.abm6393
Schöndorf DC, Ivanyuk D, Baden P, et al.: The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease. Cell reports. 2018, 23:2976-2988. 10.1016/j.celrep.2018.05.009
Mischley LK, Shankland E, Liu SZ, et al.: ATP and NAD+ Deficiency in Parkinson's Disease. Nutrients. 2023, 15 (4):943. 10.3390/nu15040943
Bonifati V, Dekker MC, Vanacore N, et al.: Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022, 23 Suppl 2:59-60. 10.1007/s100720200069
Lehmann S, Loh SH, Martins LM.: Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. Biology open. 2017, 6(2):141-147. 10.1242/bio.022186
Vos M, Geens A, Böhm C, et al.: Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency. . The Journal of cell biology.. 2017, 216:695-708. 10.1083/jcb.201511044
Brakedal B, Dölle C, Riemer F, et al.: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell Metab. 2022, 34:396-407. 10.1016/j.cmet.2022.02.001
A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson's Disease (NOPARK). https://www.clinicaltrials.gov/study/NCT03568968.
Conze DB, Crespo-Barreto J, Kruger CL: Safety assessment of nicotinamide riboside, a form of vitamin B3. Hum Exp Toxicol. 2016, 35:1149-1160. 10.1177/0960327115626254
Martens CR, Denman BA, Mazzo MR, et al.: Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018, 9(1):1286. 10.1038/s41467-018-03421-7
Dellinger RW, Santos SR, Morris M, et al.: Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis. 2017, 3:17. 10.1038/s41514-017-0016-9
Copyright (c) 2025 Illia Koval, Klaudia Romejko, Barbara Kujawa, Jagoda Saniuk, Sandra Sienkiewicz, Justyna Rajczyk, Weronika Kielińska, Joanna Osmólska, Michał Dorota, Kacper Wojtala
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
