Nicotinamide riboside first alleviates symptoms but later downregulates dopamine metabolism in proteasome inhibition mouse model of Parkinson's disease
Giorgio Turconi,
Farhan Alam,
Tanima SenGupta,
Sini Pirnes-Karhu,
Soophie Olfat,
Mark S. Schmidt,
Kärt Mätlik,
Ana Montaño-Rodriguez,
Vladimir Heiskanen,
Daniel Garton,
Petteri T. Piepponen,
Charles Brenner,
Carina I. Holmberg,
Hilde Nilsen,
Eija Pirinen,
Jaan-Olle Andressoo
Affiliations
Giorgio Turconi
Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland
Farhan Alam
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
Tanima SenGupta
Department of Microbiology, Oslo University Hospital PO Box 0424 Oslo, Norway and University of Oslo, The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway
Sini Pirnes-Karhu
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
Soophie Olfat
Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland
Mark S. Schmidt
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Kärt Mätlik
Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland
Ana Montaño-Rodriguez
Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland
Vladimir Heiskanen
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
Daniel Garton
Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland
Petteri T. Piepponen
Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E, 00014, University of Helsinki, Helsinki, Finland
Charles Brenner
Department of Diabetes & Cancer Metabolism, City of Hope National Medical Center, Duarte, CA, USA
Carina I. Holmberg
Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland
Hilde Nilsen
Department of Microbiology, Oslo University Hospital PO Box 0424 Oslo, Norway and University of Oslo, The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway
Eija Pirinen
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland; Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, FIN-90220, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu Finland, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Corresponding author. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland.
Jaan-Olle Andressoo
Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), 14183, Karolinska Institutet, Stockholm, Sweden; Corresponding author. Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland.
Parkinson's disease (PD) is associated with a reduction in 26/20S proteasome and mitochondrial function and depletion of dopamine. Activation of mitochondrial function with the NAD+ precursor nicotinamide riboside (NR) is a potential therapeutic for PD. However, despite recently started clinical trials, analysis of NR in mammalian animal PD models is lacking and data in simpler PD models is limited. We analyzed the effect of NR in C. elegans and in mouse 26/20S proteasome inhibition models of PD. In C. elegans, NR rescued α-synuclein overexpression induced phenotypes likely by activating the mitochondrial unfolded protein response. However, in a proteasome inhibitor-induced mouse model of PD, NR first partially rescued behavioural dysfunction, but later resulted in decrease in dopamine and its related gene expression in the substantia nigra. Our results suggest that reduction in 26/20S function with long term NR treatment may increase risk for developing reduced nigrostriatal DA function.
