PT  - JOURNAL ARTICLE
AU  - Giorgio Turconi
AU  - Farhan Alam
AU  - Tanima SenGupta
AU  - Sini Pirnes-Karhu
AU  - Soophie Olfat
AU  - Mark S. Schmidt
AU  - Kärt Mätlik
AU  - Ana Montaño-Rodriguez
AU  - Vladimir Heiskanen
AU  - Petteri T. Piepponen
AU  - Charles Brenner
AU  - Carina I. Holmberg
AU  - Hilde Nilsen
AU  - Jaan-Olle Andressoo
AU  - Eija Pirinen
TI  - Nicotinamide riboside alleviates Parkinson’s disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure
AID  - 10.1101/2021.03.12.435062
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.12.435062
4099  - http://biorxiv.org/content/early/2021/03/12/2021.03.12.435062.short
4100  - http://biorxiv.org/content/early/2021/03/12/2021.03.12.435062.full
AB  - 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 StatementCB 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.