Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways

Zhang, Chun‐Ting; Yang, Yee‐Hong; Liang, Weiwei; Wang, Tianhang; Wang, Shuyu; Wang, Xudong; Wang, Ying; Jiang, Haiyang; Feng, Honglin

doi:10.1016/j.brainresbull.2019.01.019

Cited by 35 publications

(25 citation statements)

References 91 publications

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“…It has been recently revealed that NAD+ levels decrease normally with age and involve in the support of mitochondrial health in the aged tissue [67,68]. Moreover, NAD+ levels decline with age in the hippocampus of mice, alongside the reduced expression of NAMPT [69]. To examine whether the NAD+ decline was actually involved in the pathogenic mechanism of ALS disease, we measured expression levels of key proteins, NAMPT and NMNAT3 in SOD1 G93A mice and litter-matched WT mice, respectively.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1^G93A Mice

Zhou¹,

Zhu²,

Qiu³

et al. 2020

Int. J. Biol. Sci.

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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 SOD1 G93A 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 (UPR mt ) 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 SOD1 G93A 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 SOD1 G93A 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 SOD1 G93A mice. At last, we found that levels of UPR mt related protein were significantly increased in the brain of SOD1 G93A mice after the NR treatment. In summary, these findings reveal that the administration of NR activates UPR mt signaling, modulates mitochondrial proteostasis and improves the adult neurogenesis in the brain of SOD1 G93A mice.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1^G93A Mice

Zhou¹,

Zhu²,

Qiu³

et al. 2020

Int. J. Biol. Sci.

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“…Through functional enrichment analysis of these regulated genes, we found enrichment for the following terms: GO:0006623: protein targeting to vacuole, GO: 0016050: vesicle organization, hsa04064: NF-κB signalling pathway, and GO: 0006352: DNA-templated transcription and initiation (Figure 4(b)). Notably, it has been reported that some genes regulated by MALAT1 are involved in the pathogenesis of ALS, including DECR1 [26], CPEB4 [27], VPS37A [28], SP1 [10,29], EEA1 [30], RB1 [31], and GCLC [32] (Figure 4(a)).…”

Section: Cerna Network Function Annotationmentioning

confidence: 99%

The Novel Regulatory Role of lncRNA-miRNA-mRNA Axis in Amyotrophic Lateral Sclerosis: An Integrated Bioinformatics Analysis

Zuo

Zhang

Zhao

et al. 2021

Computational and Mathematical Methods in Medicine

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that primarily affects motor neurons, causing muscle atrophy, bulbar palsy, and pyramidal tract signs. However, the aetiology and pathogenesis of ALS have not been elucidated to date. In this study, a competitive endogenous RNA (ceRNA) network was constructed by analyzing the expression profiles of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) that were matched by 7 ALS samples and 4 control samples, and then a protein-protein interaction (PPI) network was constructed to identify the genes related to ALS. Gene Ontology (GO) was used to study the potential functions of differentially expressed mRNAs (DEmRNAs) in the ceRNA network. For the ALS and control groups, 247177 potential lncRNA-mRNA ceRNA relationship pairs were screened. Analysis of significant relationship pairs demonstrated that the PPI modules formed by the MALAT1-regulated SYNRG, ITSN2, PICALM, AP3B1, and AAK1 genes may play important roles in the pathogenesis of ALS, and these results may help to characterize the pathogenesis of ALS.

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“…In addition, application of advanced genetic techniques has permitted the identification of interacting loci for known ALS genes [131][132][133][134][135]. These genetic interactions, in turn, have provided insights into the molecular mechanisms underlying neurodegeneration in ALS patients and provide a platform for the assaying of potential ALS therapeutics [136].…”

Section: Ectopic Expression Of Wild Type and Disease Variants Adultmentioning

confidence: 99%

Modeling Neurodegenerative Disorders in Drosophila melanogaster

Bolus

Crocker

Boekhoff-Falk

et al. 2020

IJMS

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Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using Drosophila models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders.

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Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways

Cited by 35 publications

References 91 publications

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1^G93A Mice

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1^G93A Mice

The Novel Regulatory Role of lncRNA-miRNA-mRNA Axis in Amyotrophic Lateral Sclerosis: An Integrated Bioinformatics Analysis

Modeling Neurodegenerative Disorders in Drosophila melanogaster

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Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways

Cited by 35 publications

References 91 publications

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1G93A Mice

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1G93A Mice

The Novel Regulatory Role of lncRNA-miRNA-mRNA Axis in Amyotrophic Lateral Sclerosis: An Integrated Bioinformatics Analysis

Modeling Neurodegenerative Disorders in Drosophila melanogaster

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Product

Resources

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Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1^G93A Mice

Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1^G93A Mice