scholarly journals Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection

2021 ◽  
Author(s):  
Yo Sasaki ◽  
Jian Zhu ◽  
Yun Shi ◽  
Weixi Gu ◽  
Bostjan Kobe ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Neurodegenerative Disorders ◽  
Axon Degeneration ◽  
Biosynthetic Enzyme ◽  
Allosteric Site ◽  
Nicotinamide Mononucleotide ◽  
Bacterial Enzyme ◽  
Axon Loss ◽  
Metabolic Sensor

SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN competes with NMN for binding to the SARM1 allosteric site, that NaMN inhibits SARM1 activation, and that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.

scholarly journals Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration

2018 ◽  
Vol 115 (42) ◽  
pp. 10654-10659 ◽  
Author(s):  
Hui-wen Liu ◽  
Chadwick B. Smith ◽  
Mark S. Schmidt ◽  
Xiaolu A. Cambronne ◽  
Michael S. Cohen ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Dorsal Root ◽  
Therapeutic Strategy ◽  
Alternative Pathway ◽  
Axon Degeneration ◽  
Salvage Pathway ◽  
Drg Neurons ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Mononucleotide ◽  
Bacterial Enzyme

Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy (CIPN), is thought to be caused by a loss of the essential metabolite nicotinamide adenine dinucleotide (NAD+) via the prodegenerative protein SARM1. Some studies challenge this notion, however, and suggest that an aberrant increase in a direct precursor of NAD+, nicotinamide mononucleotide (NMN), rather than loss of NAD+, is responsible. In support of this idea, blocking NMN accumulation in neurons by expressing a bacterial NMN deamidase protected axons from degeneration. We hypothesized that protection could similarly be achieved by reducing NMN production pharmacologically. To achieve this, we took advantage of an alternative pathway for NAD+ generation that goes through the intermediate nicotinic acid mononucleotide (NAMN), rather than NMN. We discovered that nicotinic acid riboside (NAR), a precursor of NAMN, administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase that produces NMN, protected dorsal root ganglion (DRG) axons against vincristine-induced degeneration as well as NMN deamidase. Introducing a different bacterial enzyme that converts NAMN to NMN reversed this protection. Collectively, our data indicate that maintaining NAD+ is not sufficient to protect DRG neurons from vincristine-induced axon degeneration, and elevating NMN, by itself, is not sufficient to cause degeneration. Nonetheless, the combination of FK866 and NAR, which bypasses NMN formation, may provide a therapeutic strategy for neuroprotection.

scholarly journals Neurotoxin-mediated ­­potent activation of the axon degeneration regulator SARM1

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Andrea Loreto ◽  
Carlo Angeletti ◽  
Weixi Gu ◽  
Andrew Osborne ◽  
Bart Nieuwenhuis ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Neurodegenerative Disorders ◽  
Nicotinamide Adenine Dinucleotide ◽  
Genetic Mutation ◽  
Axon Degeneration ◽  
Regulatory Domain ◽  
Axon Loss ◽  
Induced Neuron

Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor. Removal of SARM1 completely rescues mouse neurons from vacor-induced neuron and axon death in vitro and in vivo. We present the crystal structure the Drosophila SARM1 regulatory domain complexed with this activator, the vacor metabolite VMN, which as the most potent activator yet know is likely to support drug development for human SARM1 and NMNAT2 disorders. This study indicates the mechanism of neurotoxicity and pesticide action by vacor, raises important questions about other pyridines in wider use today, provides important new tools for drug discovery, and demonstrates that removing SARM1 can robustly block programmed axon death induced by toxicity as well as genetic mutation.

Hydrogen Sulfide in Physiological and Pathological Mechanisms in Brain

2018 ◽  
Vol 17 (9) ◽  
pp. 654-670 ◽  
Author(s):  
Mohit Kumar ◽  
Rajat Sandhir
Keyword(s):  
Nitric Oxide ◽  
Traumatic Brain Injury ◽  
Hydrogen Sulfide ◽  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Scientific Community ◽  
Molecular Targets ◽  
Long Term Potentiation ◽  
Term Potentiation

Background & Objective: Hydrogen sulfide [H2S] has been widely known as a toxic gas for more than 300 years in the scientific community. However, the understanding about this small molecule has changed after the discovery of involvement of H2S in physiological and pathological mechanisms in brain. H2S is a third gasotransmitter and neuromodulator after carbon monoxide [CO] and nitric oxide [NO]. H2S plays an important role in memory and cognition by regulating long-term potentiation [LTP] and calcium homeostasis in neuronal cells. The disturbances in endogenous H2S levels and trans-sulfuration pathway have been implicated in neurodegenerative disorders like Alzheimer’s disease, Parkinson disease, stroke and traumatic brain injury. According to the results obtained from various studies, H2S not only behaves as neuromodulator but also is a potent antioxidant, anti-inflammatory and anti-apoptotic molecule suggesting its neuroprotective potential. Conclusion: Recently, there is an increased interest in developing H2S releasing pharmaceuticals to target various neurological disorders. This review covers the information about the involvement of H2S in neurodegenerative diseases, its molecular targets and its role as potential therapeutic molecule.

Neuroprotective Role of Nutritional Supplementation in Athletes

2021 ◽  
Vol 14 ◽  
Author(s):  
Supriya Mishra ◽  
Vikram Jeet Singh ◽  
Pooja A Chawla ◽  
Viney Chawla
Keyword(s):  
Neurodegenerative Disorders ◽  
Brain Injuries ◽  
Recovery Process ◽  
Traumatic Brain Injuries ◽  
Omega 3 ◽  
Long Run ◽  
Pathological Mechanism ◽  
Injury Recovery

Background: Neurodegenerative disorders belong to different classes of progressive/chronic conditions that affect the peripheral/central nervous system. It has been shown through studies that athletes who play sports involving repeated head trauma and sub-concussive impacts are more likely to experience neurological impairments and neurodegenerative disorders in the long run. Aims: The aim of the current narrative review article is to provide a summary of various nutraceuticals that offer promise in the prevention or management of sports-related injuries, especially concussions and mild traumatic brain injuries. Methods: This article reviews the various potential nutraceutical agents and their possible mechanisms in providing a beneficial effect in the injury recovery process. A thorough survey of the literature was carried out in the relevant databases to identify studies published in recent years. In the present article, we have also highlighted the major neurological disorders along with the associated nutraceutical(s) therapy in the management of disorders. Results: The exact pathological mechanism behind neurodegenerative conditions is complex as well as idiopathic. However, mitochondrial dysfunction, oxidative stress as well as intracellular calcium overload are some common reasons responsible for the progression of these neurodegenerative disorders. Owing to the multifaceted effects of nutraceuticals (complementary medicine), these supplements have gained importance as neuroprotective. These diet-based approaches inhibit different pathways in a physiological manner without eliciting adverse effects. Food habits and lifestyle of an individual also affect neurodegeneration. Conclusion: Studies have shown nutraceuticals (such as resveratrol, omega-3-fatty acids) to be efficacious in terms of their neuroprotection against several neurodegenerative disorders and to be used as supplements in the management of traumatic brain injuries. Protection prior to injuries is needed since concussions or sub-concussive impacts may trigger several pathophysiological responses or cascades that can lead to long-term complications associated with CNS. Thus, the use of nutraceuticals as prophylactic treatment for neurological interventions has been proposed.

Time Required to Achieve Homogeneity of Test Substances Added to Dog Feed

1991 ◽  
Vol 74 (5) ◽  
pp. 857-861
Author(s):  
Philip P Sapienza ◽  
George J Ikeda ◽  
Patricia I Warr ◽  
Richard H Albert
Keyword(s):  
Nicotinic Acid ◽  
Animal Feed ◽  
Mixing Time ◽  
Critical Factor ◽  
Laboratory Animals ◽  
Time Period ◽  
Time Test ◽  
Time Required ◽  
Carrier Animal

Abstract The homogeneity of test substances in a carrier (animal feed) is a critical factor In conducting long-term feeding studies in laboratory animals. A method for determining the adequate amount of mixing to achieve homogeneity by a mixer of the type described has been determined when 2 distinctly different compounds are added to ground dog feed. Nicotinic acid and butylated hydroxyanlsole at a concentration of 1% were separately mixed with the dog feed for 15,30,45,60, and 120 min to determine optimum mixing time. Test portions were taken from 4 different sampling sites at each time period and analyzed in duplicate for the added substance. Four batches were prepared and the results were aggregated. Very little interbatch variability was observed. The variance of the average values from the 4 sampling sites at each time period was calculated and used as a simple, crude, but effective numerical quantity to monitor the approach to homogeneity of the mixture.

scholarly journals Identification of the Escherichia coliNicotinic Acid Mononucleotide Adenylyltransferase Gene

2000 ◽  
Vol 182 (15) ◽  
pp. 4372-4374 ◽  
Author(s):  
Ryan A. Mehl ◽  
Cynthia Kinsland ◽  
Tadhg P. Begley
Keyword(s):  
Escherichia Coli ◽  
Product Inhibition ◽  
Biosynthetic Enzyme ◽  
Nicotinamide Mononucleotide

ABSTRACT The gene (ybeN) coding for nicotinate mononucleotide adenylyltransferase, an NAD(P) biosynthetic enzyme, has been identified and overexpressed in Escherichia coli. This enzyme catalyzes the reversible adenylation of nicotinate mononucleotide and shows product inhibition. The rate of adenylation of nicotinate mononucleotide is at least 20 times faster than the rate of adenylation of nicotinamide mononucleotide.

scholarly journals MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Romina Aron Badin ◽  
Aurore Bugi ◽  
Susannah Williams ◽  
Marta Vadori ◽  
Marie Michael ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Neurodegenerative Disorders ◽  
Therapeutic Approaches ◽  
Primate Model ◽  
Term Survival ◽  
Neural Grafts ◽  
Neuro Inflammation ◽  
Hla Haplotypes

Abstract Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington’s disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain.

scholarly journals GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1683
Author(s):  
Octavio Silva-García ◽  
Ricarda Cortés-Vieyra ◽  
Francisco N. Mendoza-Ambrosio ◽  
Guillermo Ramírez-Galicia ◽  
Víctor M. Baizabal-Aguirre
Keyword(s):  
Neurodegenerative Disorders ◽  
Glycogen Synthase ◽  
Similar Efficacy ◽  
Glycogen Synthase Kinase 3 ◽  
Brain Functions ◽  
Chemical Inhibitors ◽  
Simultaneous Inhibition ◽  
The Brain

The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer’s disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3β kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α.

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