Int J Biol Sci 2020; 16(2):284-297. doi:10.7150/ijbs.38487
Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1G93A Mice
1. Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
2. Department of Neurology, First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
*These authors contributed equally to this work.
Zhou Q, Zhu L, Qiu W, Liu Y, Yang F, Chen W, Xu R. Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1G93A Mice. Int J Biol Sci 2020; 16(2):284-297. doi:10.7150/ijbs.38487. Available from http://www.ijbs.com/v16p0284.htm
Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, the brain stem, and the motor cortex. So far, there is still a lack of effective drugs. Nicotinamide adenine dinucleotide (NAD+) takes part in redox reactions and the NAD-dependent signaling pathway. The NAD+ decline is related with many neurological diseases, leading to the accumulation of neurotoxic protein in the central nervous system. Moreover, the NAD+ supplementation is shown to promote neural stem cells/neuronal precursor cells (NSCs/NPCs) pool maintenance. Regulatory mechanisms and functions of NAD+ metabolism in ALS are still unknown. Thus, we hypothesized the aggregation of human SOD1 toxic protein and the fate of NSCs/NPCs in the ALS disease could be improved by the administration of nicotinamide riboside (NR), an NAD+ precursor. In this study, we treated SOD1G93A transgenic and wild-type mice by the oral administration of 20 mg/ml NR starting at 50 days of age. Effects of NR on the body weight, the motor function, the onset and the survival were assessed during the experiment. The expression of mutant hSOD1 protein, mitochondrial unfolded protein response (UPRmt) related protein, mitophagy markers and NAD+ metabolism related protein were detected by immunoblotting. Effects of NR on the NSCs/NPCs in neurogenic niches of brain were identified by the immunofluorescence staining. Our investigation elucidated that the NR treatment exhibited better hanging wire endurance but did not postpone the onset or extend the life span of SOD1G93A mice. Besides, we observed that the NR repletion promoted the clearance of mitochondrial hSOD1 neurotoxic protein. Meanwhile, the mitochondrial function pathway was disrupted in the brain of SOD1G93A mice. What's more, we demonstrated that the inadequate function of NAD+ salvage synthesis pathway was the primary explanation behind the decline of NAD+, and the NR treatment enhanced the proliferation and migration of NSCs/NPCs in the brain of SOD1G93A mice. At last, we found that levels of UPRmt related protein were significantly increased in the brain of SOD1G93A mice after the NR treatment. In summary, these findings reveal that the administration of NR activates UPRmt signaling, modulates mitochondrial proteostasis and improves the adult neurogenesis in the brain of SOD1G93A mice.
Keywords: Nicotinamide riboside, Amyotrophic lateral sclerosis, Mitochondrial unfolded protein response related protein, Neural stem cells, Neuronal precursor cells