Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Astrocytes, the main non-neuronal cells in the brain, have significant roles in the maintenance and survival of neurons. Oxidative stress has been implicated in various neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Myxobacteria produce a wide range of bioactive metabolites with notable structures and modes of action, which introduce them as potent natural product producers. In the present study, we evaluated the effects of myxobacterial extracts on hydrogen peroxide (H2O2)-mediated toxicity on primary human astrocytes. We showed that myxobacterial extracts could decrease the formation of reactive oxygen species (ROS), nitric oxide (NO) production, and cell death assessed by the release of lactate dehydrogenase (LDH). Myxobacterial extracts were also able to reduce the nitric oxide synthase (NOS) activity. The extracts reduced the oxidative effect of H2O2 on over-activation of poly (ADP-ribose) polymerase (PARP1), therefore preventing the cell death by restoring the NAD+ levels. In addition, myxobacterial extracts ameliorated the oxidative stress by increasing the glutathione level in cells. The overall results showed myxobacterial extracts, especially from the strains Archangium sp. UTMC 4070 and Cystobacter sp. UTMC 4073, were able to protect human primary astrocytes from oxidative stress.
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PMID:Protective Effects of Myxobacterial Extracts on Hydrogen Peroxide-induced Toxicity on Human Primary Astrocytes. 3049 22

Sirtuins (SIRTs) are NAD+-dependent deacylases that play a key role in transcription, DNA repair, metabolism, and oxidative stress resistance. Increasing NAD+ availability regulates endogenous SIRT activity, leading to increased resistance to oxidative stress and decreased mitochondrial reactive oxygen production in multiple cell types and disease models. This protection, at least in part, depends on the activation of antioxidant mitochondrial proteins. We now show that increasing total NAD+ content in astrocytes leads to the activation of the transcription factor nuclear factor, erythroid-derived 2, like 2 (Nfe2l2 or Nrf2) and up-regulation of the antioxidant proteins heme oxygenase 1 (HO-1) and sulfiredoxin 1 (SRXN1). Nrf2 activation also occurs as a result of SIRT6 overexpression. Mutations in Cu-Zn superoxide dismutase 1 (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS). Astrocytes isolated from mutant human SOD1-overexpressing mice induce motor neuron death in coculture. Treatment with nicotinamide mononucleotide or nicotinamide riboside increases total NAD+ content in ALS astrocytes and abrogates their toxicity toward cocultured motor neurons. The observed neuroprotection depends on SIRT6 expression in astrocytes. Moreover, overexpression of SIRT6 in astrocytes by itself abrogates the neurotoxic phenotype of ALS astrocytes. Our results identify SIRT6 as a potential therapeutic target to prevent astrocyte-mediated motor neuron death in ALS.-Harlan, B. A., Pehar, M., Killoy, K. M., Vargas, M. R. Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1.
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PMID:Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1. 3084 54

The kynurenine pathway is important in cellular energy generation and limiting cellular ageing as it degrades about 90% of dietary tryptophan into the essential co-factor NAD+ (nicotinamide adenine dinucleotide). Prior to the production of NAD+, various intermediate compounds with neuroactivity (kynurenic acid, quinolinic acid) or antioxidant activity (3-hydroxykynurenine, picolinic acid) are synthesized. The kynurenine metabolites can participate in numerous neurodegenerative disorders (Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease) or other diseases such as AIDS, cancer, cardiovascular diseases, inflammation, and irritable bowel syndrome. Recently, the role of gut in affecting the emotional and cognitive centres of the brain has attracted a great deal of attention. In this review, we focus on the bidirectional communication between the gut and the brain, known as the gut-brain axis. The interaction of components of this axis, namely, the gut, its microbiota, and gut pathogens; tryptophan; the kynurenine pathway on tryptophan availability; the regulation of kynurenine metabolite concentration; and diversity and population of gut microbiota, has been considered.
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PMID:Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status. 3125 31

Macroautophagy (autophagy) is a key catabolic pathway for the maintenance of proteostasis through constant digestion of selective cargoes. The selectivity of autophagy is mediated by autophagy receptors that recognize and recruit cargoes to autophagosomes. SQSTM1/p62 is a prototype autophagy receptor, which is commonly found in protein aggregates associated with major neurodegenerative diseases. While accumulation of SQSTM1 implicates a disturbance of selective autophagy pathway, the pathogenic mechanism that contributes to impaired autophagy degradation remains poorly characterized. Herein we show that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)-linked mutations of TBK1 and SQSTM1 disrupt selective autophagy and cause neurotoxicity. Our data demonstrates that proteotoxic stress activates serine/threonine kinase TBK1, which coordinates with autophagy kinase ULK1 to promote concerted phosphorylation of autophagy receptor SQSTM1 at the UBA domain and activation of selective autophagy. In contrast, ALS-FTLD-linked mutations of TBK1 or SQSTM1 reduce SQSTM1 phosphorylation and compromise ubiquitinated cargo binding and clearance. Moreover, disease mutation SQSTM1G427R abolishes phosphorylation of Ser351 and impairs KEAP1-SQSTM1 interaction, thus diminishing NFE2L2/Nrf2-targeted gene expression and increasing TARDBP/TDP-43 associated stress granule formation under oxidative stress. Furthermore, expression of SQSTM1G427R in neurons impairs dendrite morphology and KEAP1-NFE2L2 signaling. Therefore, our results reveal a mechanism whereby pathogenic SQSTM1 mutants inhibit selective autophagy and disrupt NFE2L2 anti-oxidative stress response underlying the neurotoxicity in ALS-FTLD.Abbreviations: ALS: amyotrophic lateral sclerosis; FTLD: frontotemporal lobar degeneration; G3BP1: GTPase-activating protein (SH3 domain) binding protein 1; GSTM1: glutathione S-transferase, mu 1; HMOX/HO-1: Heme oxygenase 1; IP: immunoprecipitation; KEAP1: kelch-like ECH associated protein 1; KI: kinase inactive; KIR: KEAP1 interaction region; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MBP: maltose binding protein; NBR1: NBR1, autophagy cargo receptor; NFE2L2/Nrf2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; SQSTM1/p62: sequestosome 1; SOD1: superoxide dismutase 1, soluble; S.S.: serum starvation; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; UBA: ubiquitin association; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.
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PMID:ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. 3136 87

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer's, Parkinson's, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.
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PMID:NAD+ in Brain Aging and Neurodegenerative Disorders. 3157 33

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.
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PMID:Nicotinamide Riboside Enhances Mitochondrial Proteostasis and Adult Neurogenesis through Activation of Mitochondrial Unfolded Protein Response Signaling in the Brain of ALS SOD1G93A Mice. 3192 56

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons. Astrocytes from diverse ALS models induce motor neuron death in co-culture. Enhancing NAD+ availability, or increasing the expression of the NAD+-dependent deacylases SIRT3 and SIRT6, abrogates their neurotoxicity in cell culture models. To determine the effect of increasing NAD+ availability in ALS mouse models we used two strategies, ablation of a NAD+-consuming enzyme (CD38) and supplementation with a bioavailable NAD+ precursor (nicotinamide riboside, NR). Deletion of CD38 had no effect in the survival of two hSOD1-linked ALS mouse models. On the other hand, NR-supplementation delayed motor neuron degeneration, decreased markers of neuroinflammation in the spinal cord, appeared to modify muscle metabolism and modestly increased the survival of hSOD1G93A mice. In addition, we found altered expression of enzymes involved in NAD+ synthesis (NAMPT and NMNAT2) and decreased SIRT6 expression in the spinal cord of ALS patients, suggesting deficits of this neuroprotective pathway in the human pathology. Our data denotes the therapeutic potential of increasing NAD+ levels in ALS. Moreover, the results indicate that the approach used to enhance NAD+ levels critically defines the biological outcome in ALS models, suggesting that boosting NAD+ levels with the use of bioavailable precursors would be the preferred therapeutic strategy for ALS.
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PMID:Evaluation of the NAD+ biosynthetic pathway in ALS patients and effect of modulating NAD+ levels in hSOD1-linked ALS mouse models. 3201 38

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD+) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.
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PMID:Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review. 3211 73

Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half after the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. The balance between axon survival and self-destruction is intimately tied to axonal NAD+ metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson's.
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PMID:The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease. 3231 48

Amyotrophic lateral sclerosis (ALS) is a common degenerative disease of the central nervous system concerning a progressive loss of upper and lower motor neurons. While 5%-10% of patients are diagnosed with the inherited form of the disease, the vast majority of patients suffer from the less characterized sporadic form of ALS (sALS). As the wobbler mouse and the ALS show striking similarities in view of phenotypical attributes, the mouse is rated as an animal model for the disease. Recent investigations show the importance of nicotinamide adenine dinucleotide (NAD+) and its producing enzyme nicotinic acid mononucleotide transferase 2 (Nmnat2) for neurodegeneration as well as for the preservation of health of the neuronal cells. Furthermore, it is newly determined that these molecules show significant downregulations in the spinal cord of wobbler mice in the stable phase of disease development. Here, we were able to prove a positive benefit on affected motor neurons from an additional NAD+ supply as well as an increase in the Nmnat2 level through caffeine treatment in cells in vitro. In addition, first assumptions about the importance of endogenous and exogenous factors that have an influence on the wellbeing of motor nerve cells in the model of ALS can be considered.
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PMID:Caffeine and NAD+ Improve Motor Neural Integrity of Dissociated Wobbler Cells In Vitro. 3247 Dec 90


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