title: S-nitrosothiol depletion in amyotrophic lateral sclerosis.
abstract: Recent data suggest that either excessive or deficient levels of protein S-nitrosylation may contribute to disease. Disruption of S-nitrosothiol (SNO) homeostasis may result not only from altered nitric oxide (NO) synthase activity but also from alterations in the activity of denitrosylases that remove NO groups. A subset of patients with familial amyotrophic lateral sclerosis (ALS) have mutations in superoxide dismutase 1 (SOD1) that increase the denitrosylase activity of SOD1. Here, we show that the increased denitrosylase activity of SOD1 mutants leads to an aberrant decrease in intracellular protein and peptide S-nitrosylation in cell and animal models of ALS. Deficient S-nitrosylation is particularly prominent in the mitochondria of cells expressing SOD1 mutants. Our results suggest that SNO depletion disrupts the function and/or subcellular localization of proteins that are regulated by S-nitrosylation such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and thereby contributes to ALS pathogenesis. Repletion of intracellular SNO levels with SNO donor compounds rescues cells from mutant SOD1-induced death. These results suggest that aberrant depletion of intracellular SNOs contributes to motor neuron death in ALS, and raises the possibility that deficient S-nitrosylation is a general mechanism of disease pathogenesis. SNO donor compounds may provide new therapeutic options for diseases such as ALS that are associated with deficient S-nitrosylation.
authors.affiliation: Department of Medicine and Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Schonhoff
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Hemachand
authors.initials: H
authors.lastname: Tummala
authors.forename: Michael A
authors.initials: MA
authors.lastname: Johnson
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estevéz
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.forename: Andrés
authors.initials: A
authors.lastname: Kamaid
authors.forename: Karina C
authors.initials: KC
authors.lastname: Ricart
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: Zuoshang
authors.initials: Z
authors.lastname: Xu
authors.forename: Joan B
authors.initials: JB
authors.lastname: Mannick
mesh_terms: D021581:Active Transport, Cell Nucleus; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D009584:Nitrogen / Q000378:metabolism; D026422:S-Nitrosoglutathione / Q000378:metabolism / Q000494:pharmacology; D026403:S-Nitrosothiols / Q000032:analysis / Q000378:metabolism*; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D026403:S-Nitrosothiols; C000606290:SOD1 protein, human; D026422:S-Nitrosoglutathione; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D009584:Nitrogen