S -nitrosothiol depletion in amyotrophic lateral sclerosis

doi:10.1073/pnas.0507243103

S-nitrosothiol depletion in amyotrophic lateral sclerosis

*Departments of Medicine and Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605;
^†Department of Pharmacology and Neuroscience, KEIO University School of Medicine, Tokyo 160-8582, Japan;
^‡Departments of Pediatrics and Chemistry, University of Virginia, Charlottesville, VA 22904; and
^§Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 21, 2005 (received for review August 19, 2005)

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.

Footnotes

^¶To whom correspondence should be addressed at:
University of Massachusetts Medical School, Lazare Research Building Room 222, 364 Plantation Street, Worcester, MA 01605.
E-mail: joan.mannick{at}umassmed.edu
Author contributions: M.M., M.A.J., A.G.E., B.G., T.L.M., and J.B.M. designed research; C.M.S., M.M., H.T., M.A.J., R.W., A.K., K.C.R., Y.H., and J.B.M. performed research; M.M. and Z.X. contributed new reagents/analytic tools; C.M.S., M.A.J., A.G.E., B.G., T.L.M., and J.B.M. analyzed data; and J.B.M. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

SNO,

S-nitrosothiol;

SOD,

superoxide dismutase;

GSNO,

S-nitrosoglutathione;

SNOC,

S-nitrosocysteine;

SNAP,

S-nitroso-N-acetylpenicillamine.