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Nicotinamide riboside alleviates Parkinson’s disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure

View ORCID ProfileGiorgio Turconi, Farhan Alam, Tanima SenGupta, Sini Pirnes-Karhu, Soophie Olfat, View ORCID ProfileMark S. Schmidt, View ORCID ProfileKärt Mätlik, Ana Montaño-Rodriguez, Vladimir Heiskanen, View ORCID ProfilePetteri T. Piepponen, View ORCID ProfileCharles Brenner, View ORCID ProfileCarina I. Holmberg, View ORCID ProfileHilde Nilsen, View ORCID ProfileJaan-Olle Andressoo, View ORCID ProfileEija Pirinen
doi: https://doi.org/10.1101/2021.03.12.435062
Giorgio Turconi
1Department of Pharmacology, Faculty of Medicine & Helsinki Institute of Life Science, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland.
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Farhan Alam
2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.
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Tanima SenGupta
3Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway; The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway.
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Sini Pirnes-Karhu
2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.
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Soophie Olfat
1Department of Pharmacology, Faculty of Medicine & Helsinki Institute of Life Science, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland.
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Mark S. Schmidt
4Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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Kärt Mätlik
1Department of Pharmacology, Faculty of Medicine & Helsinki Institute of Life Science, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland.
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Ana Montaño-Rodriguez
1Department of Pharmacology, Faculty of Medicine & Helsinki Institute of Life Science, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland.
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Vladimir Heiskanen
2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.
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Petteri T. Piepponen
5Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E, 00014, University of Helsinki, Helsinki, Finland.
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Charles Brenner
6Department of Diabetes & Cancer Metabolism, City of Hope National Medical Center, Duarte, CA, USA.
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Carina I. Holmberg
7Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
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Hilde Nilsen
3Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway; The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway.
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Jaan-Olle Andressoo
1Department of Pharmacology, Faculty of Medicine & Helsinki Institute of Life Science, Haartmaninkatu 8, 00014, University of Helsinki, Helsinki, Finland.
8Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), 14183, Karolinska Institutet, Stockholm, Sweden.
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  • For correspondence: jaan-olle.andressoo@helsinki.fi eija.pirinen@helsinki.fi
Eija Pirinen
2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland.
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  • For correspondence: jaan-olle.andressoo@helsinki.fi eija.pirinen@helsinki.fi
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Abstract

Activation of mitochondrial metabolism and proteostasis with the NAD+ precursor nicotinamide riboside (NR) has emerged as a potential therapeutic approach for neurodegenerative disorders including Parkinson’s disease (PD). However, despite recently started clinical trials, studies on NR in animal models of PD are scarce. In this study, we investigated the effect of NR in multiple models of PD. In transgenic C. elegans overexpressing α-synuclein, a protein of which aggregation is believed to promote PD, NR rescued PD-like phenotypes including mitochondrial dysfunction and motility defects, decreased oxidative stress, and age-related dopamine (DA) neuron loss. We found that NR eased symptoms of disease by activating the mitochondrial unfolded protein response (UPRmt) via the transcription factor atfs-1. Similarly, in a proteasome inhibitor, lactacystin, -induced mouse model of PD, NR rescued mitochondrial dysfunction and behavioural deficits caused by lactacystin lesion. However, long-term NR supplementation, in conjunction with proteasome inhibition, resulted in decreased DA levels in both the lesioned and unlesioned sides of the substantia nigra with concomitant downregulation of key genes in DA metabolism. Our results suggest specific endpoints that should be monitored in ongoing NR clinical trials.

Competing Interest Statement

CB owns stock in and serves as chief scientific advisor for ChromaDex, Inc. He also consults for Ridgeline Therapeutics and Cytokinetics and is a co-founder of Athena Therapeutics. Other authors declare no conflict of interest.

Footnotes

  • ↵§ Authors share co-senior authorship.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Nicotinamide riboside alleviates Parkinson’s disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure
Giorgio Turconi, Farhan Alam, Tanima SenGupta, Sini Pirnes-Karhu, Soophie Olfat, Mark S. Schmidt, Kärt Mätlik, Ana Montaño-Rodriguez, Vladimir Heiskanen, Petteri T. Piepponen, Charles Brenner, Carina I. Holmberg, Hilde Nilsen, Jaan-Olle Andressoo, Eija Pirinen
bioRxiv 2021.03.12.435062; doi: https://doi.org/10.1101/2021.03.12.435062
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Nicotinamide riboside alleviates Parkinson’s disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure
Giorgio Turconi, Farhan Alam, Tanima SenGupta, Sini Pirnes-Karhu, Soophie Olfat, Mark S. Schmidt, Kärt Mätlik, Ana Montaño-Rodriguez, Vladimir Heiskanen, Petteri T. Piepponen, Charles Brenner, Carina I. Holmberg, Hilde Nilsen, Jaan-Olle Andressoo, Eija Pirinen
bioRxiv 2021.03.12.435062; doi: https://doi.org/10.1101/2021.03.12.435062

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