S-nitrosothiol depletion in amyotrophic lateral sclerosis

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Department of Medicine, Division of Infectious Diseases and Immunology



Document Type



Active Transport, Cell Nucleus; Amyotrophic Lateral Sclerosis; Animals; Cell Nucleus; Cells, Cultured; Copper; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Mice; Mice, Transgenic; Mitochondria; Mutation; Nitrogen; S-Nitrosoglutathione; S-Nitrosothiols; Spinal Cord; Superoxide Dismutase


Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology


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.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2404-9. Epub 2006 Feb 6. Link to article on publisher's site

DOI of Published Version


Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID