S-nitrosothiol depletion in amyotrophic lateral sclerosis

UMMS Affiliation

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

Publication Date


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.

DOI of Published Version



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

Journal/Book/Conference Title

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

Related Resources

Link to Article in PubMed

PubMed ID