RT Journal Article
SR Electronic
T1 Nicotinamide riboside alleviates Parkinson’s disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.12.435062
DO 10.1101/2021.03.12.435062
A1 Giorgio Turconi
A1 Farhan Alam
A1 Tanima SenGupta
A1 Sini Pirnes-Karhu
A1 Soophie Olfat
A1 Mark S. Schmidt
A1 Kärt Mätlik
A1 Ana Montaño-Rodriguez
A1 Vladimir Heiskanen
A1 Petteri T. Piepponen
A1 Charles Brenner
A1 Carina I. Holmberg
A1 Hilde Nilsen
A1 Jaan-Olle Andressoo
A1 Eija Pirinen
YR 2021
UL http://biorxiv.org/content/early/2021/03/12/2021.03.12.435062.abstract
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.