QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (170) Citing Articles via Google Scholar Google Scholar Articles by Paxinou, E. Articles by Ischiropoulos, H. Search for Related Content PubMed PubMed Citation Articles by Paxinou, E. Articles by Ischiropoulos, H.

 Previous Article  |  Next Article 

The Journal of Neuroscience, October 15, 2001, 21(20):8053-8061

Induction of -Synuclein Aggregation by Intracellular Nitrative Insult

Evgenia Paxinou¹, Qiping Chen¹, Marie Weisse¹, Benoit I. Giasson², Erin H. Norris², Susan M. Rueter², John Q. Trojanowski², Virginia M.-Y. Lee², and Harry Ischiropoulos¹

¹ Stokes Research Institute and Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania 19104, and ² Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania 19104

Brain lesions containing filamentous and aggregated -synuclein are hallmarks of neurodegenerative synucleinopathies. Oxidative stress has been implicated in the formation of these lesions. Using HEK 293 cells stably transfected with wild-type and mutant -synuclein, we demonstrated that intracellular generation of nitrating agents results in the formation of -synuclein aggregates. Cells were exposed simultaneously to nitric oxide- and superoxide-generating compounds, and the intracellular formation of peroxynitrite was demonstrated by monitoring the oxidation of dihydrorhodamine 123 and the nitration of -synuclein. Light microscopy using antibodies against -synuclein and electron microscopy revealed the presence of perinuclear aggregates under conditions in which peroxynitrite was generated but not when cells were exposed to nitric oxide- or superoxide-generating compounds separately. -Synuclein aggregates were observed in 20-30% of cells expressing wild-type or A53T mutant -synuclein and in 5% of cells expressing A30P mutant -synuclein. No evidence of synuclein aggregation was observed in untransfected cells or cells expressing -synuclein. In contrast, selective inhibition of the proteasome resulted in the formation of aggregates detected with antibodies to ubiquitin in the majority of the untransfected cells and cells expressing -synuclein. However, -synuclein did not colocalize with these aggregates, indicating that inhibition of the proteasome does not promote -synuclein aggregation. In addition, proteasome inhibition did not alter the steady-state levels of -synuclein, but addition of the lysosomotropic agent ammonium chloride significantly increased the amount of -synuclein, indicating that lysosomes are involved in degradation of -synuclein. Our data indicate that nitrative and oxidative insult may initiate pathogenesis of -synuclein aggregates.

Key words: superoxide; nitric oxide; peroxynitrite; -synuclein aggregation; ubiquitin; proteasome; Parkinson's disease.

---

Copyright © 2001 Society for Neuroscience  0270-6474/01/21208053-09$05.00/0

This article has been cited by other articles:

				A. D. Reynolds, D. K. Stone, R. L. Mosley, and H. E. Gendelman Nitrated {alpha}-Synuclein-Induced Alterations in Microglial Immunity Are Regulated by CD4+ T Cell Subsets J. Immunol., April 1, 2009; 182(7): 4137 - 4149. [Abstract] [Full Text] [PDF]

				L. M. Igaz, L. K. Kwong, A. Chen-Plotkin, M. J. Winton, T. L. Unger, Y. Xu, M. Neumann, J. Q. Trojanowski, and V. M.-Y. Lee Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies J. Biol. Chem., March 27, 2009; 284(13): 8516 - 8524. [Abstract] [Full Text] [PDF]

				T. Vogiatzi, M. Xilouri, K. Vekrellis, and L. Stefanis Wild Type {alpha}-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells J. Biol. Chem., August 29, 2008; 283(35): 23542 - 23556. [Abstract] [Full Text] [PDF]

				W. Zhou, J. B. Milder, and C. R. Freed Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human {alpha}-Synuclein: A PROGRESSIVE NEURODEGENERATIVE MODEL OF DIFFUSE LEWY BODY DISEASE J. Biol. Chem., April 11, 2008; 283(15): 9863 - 9870. [Abstract] [Full Text] [PDF]

				J. T. Lee, T. C. Wheeler, L. Li, and L.-S. Chin Ubiquitination of {alpha}-synuclein by Siah-1 promotes {alpha}-synuclein aggregation and apoptotic cell death Hum. Mol. Genet., March 15, 2008; 17(6): 906 - 917. [Abstract] [Full Text] [PDF]

				R. Rott, R. Szargel, J. Haskin, V. Shani, A. Shainskaya, I. Manov, E. Liani, E. Avraham, and S. Engelender Monoubiquitylation of {alpha}-Synuclein by Seven in Absentia Homolog (SIAH) Promotes Its Aggregation in Dopaminergic Cells J. Biol. Chem., February 8, 2008; 283(6): 3316 - 3328. [Abstract] [Full Text] [PDF]

				H. Nakajima, W. Amano, A. Fujita, A. Fukuhara, Y.-T. Azuma, F. Hata, T. Inui, and T. Takeuchi The Active Site Cysteine of the Proapoptotic Protein Glyceraldehyde-3-phosphate Dehydrogenase Is Essential in Oxidative Stress-induced Aggregation and Cell Death J. Biol. Chem., September 7, 2007; 282(36): 26562 - 26574. [Abstract] [Full Text] [PDF]

				B. M. Dufty, L. R. Warner, S. T. Hou, S. X. Jiang, T. Gomez-Isla, K. M. Leenhouts, J. T. Oxford, M. B. Feany, E. Masliah, and T. T. Rohn Calpain-Cleavage of {alpha}-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation Am. J. Pathol., May 1, 2007; 170(5): 1725 - 1738. [Abstract] [Full Text] [PDF]

				Y. Ye, C. Quijano, K. M. Robinson, K. C. Ricart, A. L. Strayer, M. A. Sahawneh, J. J. Shacka, M. Kirk, S. Barnes, M. A. Accavitti-Loper, et al. Prevention of Peroxynitrite-induced Apoptosis of Motor Neurons and PC12 Cells by Tyrosine-containing Peptides J. Biol. Chem., March 2, 2007; 282(9): 6324 - 6337. [Abstract] [Full Text] [PDF]

				K. Uryu, C. Richter-Landsberg, W. Welch, E. Sun, O. Goldbaum, E. H. Norris, C.-T. Pham, I. Yazawa, K. Hilburger, M. Micsenyi, et al. Convergence of Heat Shock Protein 90 with Ubiquitin in Filamentous {alpha}-Synuclein Inclusions of {alpha}-Synucleinopathies Am. J. Pathol., March 1, 2006; 168(3): 947 - 961. [Abstract] [Full Text] [PDF]

				C. W. Shults Lewy bodies PNAS, February 7, 2006; 103(6): 1661 - 1668. [Abstract] [Full Text] [PDF]

				L. J. Martin, Y. Pan, A. C. Price, W. Sterling, N. G. Copeland, N. A. Jenkins, D. L. Price, and M. K. Lee Parkinson's Disease {alpha}-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death J. Neurosci., January 4, 2006; 26(1): 41 - 50. [Abstract] [Full Text] [PDF]

				C. Wang, H. S. Ko, B. Thomas, F. Tsang, K. C.M. Chew, S.-P. Tay, M. W.L. Ho, T.-M. Lim, T.-W. Soong, O. Pletnikova, et al. Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function Hum. Mol. Genet., December 15, 2005; 14(24): 3885 - 3897. [Abstract] [Full Text] [PDF]

				H. Zhang, Y. Xu, J. Joseph, and B. Kalyanaraman Intramolecular Electron Transfer between Tyrosyl Radical and Cysteine Residue Inhibits Tyrosine Nitration and Induces Thiyl Radical Formation in Model Peptides Treated with Myeloperoxidase, H2O2, and NO2-: EPR SPIN TRAPPING STUDIES J. Biol. Chem., December 9, 2005; 280(49): 40684 - 40698. [Abstract] [Full Text] [PDF]

				F. Sun, V. Anantharam, C. Latchoumycandane, A. Kanthasamy, and A. G. Kanthasamy Dieldrin Induces Ubiquitin-Proteasome Dysfunction in {alpha}-Synuclein Overexpressing Dopaminergic Neuronal Cells and Enhances Susceptibility to Apoptotic Cell Death J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 69 - 79. [Abstract] [Full Text] [PDF]

				S. Z. Imam, J. Jankovic, S. F. Ali, J. T. Skinner, W. Xie, O. M. Conneely, and W.-D. Le Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice FASEB J, September 1, 2005; 19(11): 1441 - 1450. [Abstract] [Full Text] [PDF]

				E. H. Norris, B. I. Giasson, R. Hodara, S. Xu, J. Q. Trojanowski, H. Ischiropoulos, and V. M.-Y. Lee Reversible Inhibition of {alpha}-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations J. Biol. Chem., June 3, 2005; 280(22): 21212 - 21219. [Abstract] [Full Text] [PDF]

				W. Li, N. West, E. Colla, O. Pletnikova, J. C. Troncoso, L. Marsh, T. M. Dawson, P. Jakala, T. Hartmann, D. L. Price, et al. Aggregation promoting C-terminal truncation of {alpha}-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations PNAS, February 8, 2005; 102(6): 2162 - 2167. [Abstract] [Full Text] [PDF]

				R. Hodara, E. H. Norris, B. I. Giasson, A. J. Mishizen-Eberz, D. R. Lynch, V. M.-Y. Lee, and H. Ischiropoulos Functional Consequences of {alpha}-Synuclein Tyrosine Nitration: DIMINISHED BINDING TO LIPID VESICLES AND INCREASED FIBRIL FORMATION J. Biol. Chem., November 12, 2004; 279(46): 47746 - 47753. [Abstract] [Full Text] [PDF]

				A. M. Cuervo, L. Stefanis, R. Fredenburg, P. T. Lansbury, and D. Sulzer Impaired Degradation of Mutant {alpha}-Synuclein by Chaperone-Mediated Autophagy Science, August 27, 2004; 305(5688): 1292 - 1295. [Abstract] [Full Text] [PDF]

				R. M. Miller, L. M. Callahan, C. Casaceli, L. Chen, G. L. Kiser, B. Chui, T. M. Kaysser-Kranich, T. J. Sendera, C. Palaniappan, and H. J. Federoff Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra J. Neurosci., August 25, 2004; 24(34): 7445 - 7454. [Abstract] [Full Text] [PDF]

				W. Li, C. Lesuisse, Y. Xu, J. C. Troncoso, D. L. Price, and M. K. Lee Stabilization of {alpha}-Synuclein Protein with Aging and Familial Parkinson's Disease-Linked A53T Mutation J. Neurosci., August 18, 2004; 24(33): 7400 - 7409. [Abstract] [Full Text] [PDF]

				C. A. Wilson, D. D. Murphy, B. I. Giasson, B. Zhang, J. Q. Trojanowski, and V. M.-Y. Lee Degradative organelles containing mislocalized {alpha}- and {beta}-synuclein proliferate in presenilin-1 null neurons J. Cell Biol., May 10, 2004; 165(3): 335 - 346. [Abstract] [Full Text] [PDF]

				W. Zhou and C. R. Freed Tyrosine-to-Cysteine Modification of Human {alpha}-Synuclein Enhances Protein Aggregation and Cellular Toxicity J. Biol. Chem., March 12, 2004; 279(11): 10128 - 10135. [Abstract] [Full Text] [PDF]

				H.-J. Lee, F. Khoshaghideh, S. Patel, and S.-J. Lee Clearance of {alpha}-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway J. Neurosci., February 25, 2004; 24(8): 1888 - 1896. [Abstract] [Full Text] [PDF]

				M. M.K. Muqit, S. M. Davidson, M. D. Payne Smith, L. P. MacCormac, S. Kahns, P. H. Jensen, N. W. Wood, and D. S. Latchman Parkin is recruited into aggresomes in a stress-specific manner: over-expression of parkin reduces aggresome formation but can be dissociated from parkin's effect on neuronal survival Hum. Mol. Genet., January 1, 2004; 13(1): 117 - 135. [Abstract] [Full Text] [PDF]

				R. Sharon, I. Bar-Joseph, G. E. Mirick, C. N. Serhan, and D. J. Selkoe Altered Fatty Acid Composition of Dopaminergic Neurons Expressing {alpha}-Synuclein and Human Brains with {alpha}-Synucleinopathies J. Biol. Chem., December 12, 2003; 278(50): 49874 - 49881. [Abstract] [Full Text] [PDF]

				D. W. Miller, R. Ahmad, S. Hague, M. J. Baptista, R. Canet-Aviles, C. McLendon, D. M. Carter, P.-P. Zhu, J. Stadler, J. Chandran, et al. L166P Mutant DJ-1, Causative for Recessive Parkinson's Disease, Is Degraded through the Ubiquitin-Proteasome System J. Biol. Chem., September 19, 2003; 278(38): 36588 - 36595. [Abstract] [Full Text] [PDF]

				E. H. Norris, B. I. Giasson, H. Ischiropoulos, and V. M.-Y. Lee Effects of Oxidative and Nitrative Challenges on {alpha}-Synuclein Fibrillogenesis Involve Distinct Mechanisms of Protein Modifications J. Biol. Chem., July 11, 2003; 278(29): 27230 - 27240. [Abstract] [Full Text] [PDF]

				D. M. Sampathu, B. I. Giasson, A. C. Pawlyk, J. Q. Trojanowski, and V. M.-Y. Lee Ubiquitination of {alpha}-Synuclein Is Not Required for Formation of Pathological Inclusions in {alpha}-Synucleinopathies Am. J. Pathol., July 1, 2003; 163(1): 91 - 100. [Abstract] [Full Text] [PDF]

				D. M. Fries, E. Paxinou, M. Themistocleous, E. Swanberg, K. K. Griendling, D. Salvemini, J. W. Slot, H. F. G. Heijnen, S. L. Hazen, and H. Ischiropoulos Expression of Inducible Nitric-oxide Synthase and Intracellular Protein Tyrosine Nitration in Vascular Smooth Muscle Cells: ROLE OF REACTIVE OXYGEN SPECIES J. Biol. Chem., June 13, 2003; 278(25): 22901 - 22907. [Abstract] [Full Text] [PDF]

				E. Junn, R. D. Ronchetti, M. M. Quezado, S.-Y. Kim, and M. M. Mouradian Tissue transglutaminase-induced aggregation of alpha -synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies PNAS, February 18, 2003; 100(4): 2047 - 2052. [Abstract] [Full Text] [PDF]

				T. Antony, W. Hoyer, D. Cherny, G. Heim, T. M. Jovin, and V. Subramaniam Cellular Polyamines Promote the Aggregation of alpha -Synuclein J. Biol. Chem., January 24, 2003; 278(5): 3235 - 3240. [Abstract] [Full Text] [PDF]

				Z. Bebok, K. Varga, J. K. Hicks, C. J. Venglarik, T. Kovacs, L. Chen, K. M. Hardiman, J. F. Collawn, E. J. Sorscher, and S. Matalon Reactive Oxygen Nitrogen Species Decrease Cystic Fibrosis Transmembrane Conductance Regulator Expression and cAMP-mediated Cl- Secretion in Airway Epithelia J. Biol. Chem., November 1, 2002; 277(45): 43041 - 43049. [Abstract] [Full Text] [PDF]

				J. Lotharius, S. Barg, P. Wiekop, C. Lundberg, H. K. Raymon, and P. Brundin Effect of Mutant alpha -Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line J. Biol. Chem., October 4, 2002; 277(41): 38884 - 38894. [Abstract] [Full Text] [PDF]

				J. Lotharius and P. Brundin Impaired dopamine storage resulting from {alpha}-synuclein mutations may contribute to the pathogenesis of Parkinson's disease Hum. Mol. Genet., October 1, 2002; 11(20): 2395 - 2407. [Abstract] [Full Text] [PDF]

				H.-J. Lee, S. Y. Shin, C. Choi, Y. H. Lee, and S.-J. Lee Formation and Removal of alpha -Synuclein Aggregates in Cells Exposed to Mitochondrial Inhibitors J. Biol. Chem., February 8, 2002; 277(7): 5411 - 5417. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help