title: Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1).
abstract: Nicotinamide adenine dinucleotide (NAD(+)) participates in redox reactions and NAD(+)-dependent signaling pathways. Although the redox reactions are critical for efficient mitochondrial metabolism, they are not accompanied by any net consumption of the nucleotide. On the contrary, NAD(+)-dependent signaling processes lead to its degradation. Three distinct families of enzymes consume NAD(+) as substrate: poly(ADP-ribose) polymerases, ADP-ribosyl cyclases (CD38 and CD157), and sirtuins (SIRT1-7). Because all of the above enzymes generate nicotinamide as a byproduct, mammalian cells have evolved an NAD(+) salvage pathway capable of resynthesizing NAD(+) from nicotinamide. Overexpression of the rate-limiting enzyme in this pathway, nicotinamide phosphoribosyltransferase, increases total and mitochondrial NAD(+) levels in astrocytes. Moreover, targeting nicotinamide phosphoribosyltransferase to the mitochondria also enhances NAD(+) salvage pathway in astrocytes. Supplementation with the NAD(+) precursors nicotinamide mononucleotide and nicotinamide riboside also increases NAD(+) levels in astrocytes. Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Superoxide dismutase 1 (SOD1) mutations account for up to 20% of familial ALS and 1-2% of apparently sporadic ALS cases. Primary astrocytes isolated from mutant human superoxide dismutase 1-overexpressing mice as well as human post-mortem ALS spinal cord-derived astrocytes induce motor neuron death in co-culture. Increasing total and mitochondrial NAD(+) content in ALS astrocytes increases oxidative stress resistance and reverts their toxicity toward co-cultured motor neurons. Taken together, our results suggest that enhancing the NAD(+) salvage pathway in astrocytes could be a potential therapeutic target to prevent astrocyte-mediated motor neuron death in ALS.
authors.affiliation: From the Department of Cell and Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Harlan
authors.affiliation: From the Department of Cell and Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.affiliation: From the Department of Cell and Molecular Pharmacology and Experimental Therapeutics and.
authors.forename: Deep R
authors.initials: DR
authors.lastname: Sharma
authors.affiliation: South Carolina College of Pharmacy Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Gyda
authors.initials: G
authors.lastname: Beeson
authors.affiliation: South Carolina College of Pharmacy Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.affiliation: From the Department of Cell and Molecular Pharmacology and Experimental Therapeutics and vargasm@musc.edu.
authors.forename: Marcelo R
authors.initials: MR
authors.lastname: Vargas
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D009243:NAD; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: NAD biosynthesis; NAMPT; amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); astrocyte; mitochondria; oxidative stress