Nitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALS.

Increased levels of 3-nitrotyrosine in the central nervous system have been found in patients and mouse models of familial ALS (fALS), suggesting a possible use of nitrated proteins as biomarkers. We analyzed peripheral blood mononuclear cells (PBMCs), easily accessible samples, from sporadic ALS (sALS) patients and a rat model of fALS (a) to establish whether an increased level of nitrated proteins was present in PBMCs, too, and (b) to identify possible candidate biomarkers. With a proteomic approach, we identified for the first time the major overnitrated proteins in PBMCs from patients and rats at different disease stages. In the rats, their increased levels already were measured at a presymptomatic stage. Among them, actin, ATP synthase, and vinculin overlap between sALS patients and the rat model. Interestingly, in a previous study, actin and ATPase have been found overnitrated in the spinal cord of a mouse model of fALS before disease onset, suggesting their possible involvement in motor neuron degeneration. In conclusion, we observed that an increased level of nitrated proteins was not restricted to the spinal cord but also was present in peripheral cells of patients and an animal model, and that nitrated proteins are promising candidate biomarkers for early diagnosis of ALS.

[1]  C. Leffler,et al.  Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF‐alpha in cerebral vascular endothelial cells. , 2009, American journal of physiology. Cell physiology.

[2]  A. Musarò,et al.  Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. , 2008, Cell metabolism.

[3]  D. Cleveland,et al.  Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. , 2008, The Journal of clinical investigation.

[4]  H. Paulson,et al.  SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. , 2008, The Journal of clinical investigation.

[5]  H. Paulson,et al.  Redox modifier genes in amyotrophic lateral sclerosis in mice. , 2007, The Journal of clinical investigation.

[6]  Kuixing Zhang,et al.  Whole-genome analysis of sporadic amyotrophic lateral sclerosis. , 2007, The New England journal of medicine.

[7]  B. Nemchausky,et al.  Circadian distribution of serum cytokines in multiple sclerosis. , 2007, La Clinica terapeutica.

[8]  K. Hensley,et al.  On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. , 2006, Antioxidants & redox signaling.

[9]  M. McGrath,et al.  MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS) , 2006, Journal of Neuroimmunology.

[10]  L. Flury,et al.  Serum immunologic markers in multiple sclerosis patients on continuous combined therapy with beta-interferon 1a, prednisone and azathioprine , 2006, Multiple sclerosis.

[11]  S. Przedborski,et al.  The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice , 2006, Proceedings of the National Academy of Sciences.

[12]  G. Mazzini,et al.  Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS patients , 2006, Neuroscience Letters.

[13]  Y. Itoyama,et al.  Development of a rat model of amyotrophic lateral sclerosis expressing a human SOD1 transgene , 2005, Neuropathology : official journal of the Japanese Society of Neuropathology.

[14]  L. Barbeito,et al.  Mitochondria in Amyotrophic Lateral Sclerosis: A Trigger and a Target , 2005, Neurodegenerative Diseases.

[15]  M. Salmona,et al.  Protein Nitration in a Mouse Model of Familial Amyotrophic Lateral Sclerosis , 2005, Journal of Biological Chemistry.

[16]  M. McGrath,et al.  Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS) , 2005, Journal of Neuroimmunology.

[17]  K. Hahn,et al.  Vinculin modulation of paxillin–FAK interactions regulates ERK to control survival and motility , 2004, The Journal of cell biology.

[18]  Ka Bian,et al.  The nature of heme/iron-induced protein tyrosine nitration , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  T. Rohn,et al.  Inhibition of actin polymerization by peroxynitrite modulates neutrophil functional responses , 2003, Journal of leukocyte biology.

[20]  R. Radi,et al.  Peroxynitrite reactions and formation in mitochondria. , 2002, Free radical biology & medicine.

[21]  J. Rothstein,et al.  Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS) , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  K. Abe,et al.  Inducible Nitric Oxide Synthase (iNOS) and Nitrotyrosine Immunoreactivity in the Spinal Cords of Transgenic Mice with a G93A Mutant SOD1 Gene , 2001, Journal of neuropathology and experimental neurology.

[23]  R. Wolf,et al.  Myoglobin-catalyzed tyrosine nitration: no need for peroxynitrite. , 2001, Biochemical and biophysical research communications.

[24]  H. Wigzell,et al.  Disturbances in the Peripheral T‐Cell Repertoire of Patients with Motor Neuron Disease: High Levels of Activation and Indirect Evidence of Superantigen , 2001, Scandinavian journal of immunology.

[25]  J. Hartwig,et al.  Filamins as integrators of cell mechanics and signalling , 2001, Nature Reviews Molecular Cell Biology.

[26]  G. Mora,et al.  Circulating levels of tumour necrosis factor-α and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis , 2000, Neuroscience Letters.

[27]  J S Beckman,et al.  Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. , 1999, Science.

[28]  M. Torres,et al.  Function of the cytoskeleton in human neutrophils and methods for evaluation. , 1999, Journal of immunological methods.

[29]  J. Cedarbaum,et al.  The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function , 1999, Journal of the Neurological Sciences.

[30]  H. Tohgi,et al.  Remarkable increase in cerebrospinal fluid 3‐nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis , 1999, Annals of neurology.

[31]  R. Radi,et al.  Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. , 1999, Journal of immunology.

[32]  Robert H. Brown,et al.  Increased 3‐nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis , 1997, Annals of neurology.

[33]  M. Gurney,et al.  Increased 3‐nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation , 1997, Annals of neurology.

[34]  D. Price,et al.  Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Y. Itoyama,et al.  Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis. , 1997, Neurological research.

[36]  V. Bambini,et al.  Amyotrophic lateral sclerosis , 1996, Neurology.

[37]  R. Ezzell,et al.  Targeted disruption of vinculin genes in F9 and embryonic stem cells changes cell morphology, adhesion, and locomotion. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[38]  B. Brooks,et al.  El escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis , 1994, Journal of the Neurological Sciences.

[39]  M. Carson,et al.  ALS, SOD and peroxynitrite , 1993, Nature.

[40]  P. Højrup,et al.  Rapid identification of proteins by peptide-mass fingerprinting , 1993, Current Biology.

[41]  J H Hartwig,et al.  Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring , 1990, The Journal of cell biology.

[42]  B. Geiger,et al.  Vinculin, an intracellular protein localized at specialized sites where microfilament bundles terminate at cell membranes. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[43]  L. Liaudet,et al.  Nitric oxide and peroxynitrite in health and disease. , 2007, Physiological reviews.