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Oxidative Damage Linked to Neurodegeneration by Selective -Synuclein Nitration in Synucleinopathy Lesions
Benoit I. Giasson,1*John E. Duda,1*Ian V. J. Murray,1Qiping Chen,3José M. Souza,3Howard I. Hurtig,2Harry Ischiropoulos,3John Q. Trojanowski,1Virginia
M. -Y. Lee1
Aggregated -synuclein proteins form brain lesions that are
hallmarks of neurodegenerative synucleinopathies, and oxidativestress
has been implicated in the pathogenesis of some of thesedisorders.
Using antibodies to specific nitrated tyrosine residuesin
-synuclein, we demonstrate extensive and widespread accumulationsof
nitrated -synuclein in the signature inclusions of Parkinson'sdisease, dementia with Lewy bodies, the Lewy body variant of
Alzheimer'sdisease, and multiple system atrophy brains. We also show
thatnitrated -synuclein is present in the major filamentous
buildingblocks of these inclusions, as well as in the insoluble
fractionsof affected brain regions of synucleinopathies. The selectiveand specific nitration of -synuclein in these disorders providesevidence to directly link oxidative and nitrative damage to theonset
and progression of neurodegenerative synucleinopathies.
1 Center for Neurodegenerative Disease Research
and Department of Pathology and Laboratory Medicine,
2 Department of Neurology, University of
Pennsylvania, Philadelphia, PA 19104, USA.
3 Stokes
Research Institute and Department of Biochemistry and Biophysics,
Children's Hospital of Philadelphia and University of Pennsylvania,
Philadelphia, PA 19104, USA.
*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail:
vmylee{at}mail.med.upenn.edu
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In Science Magazine
LETTERS
George Perry, Jesús Avila, Michael G. Espey, David A. Wink, Craig S. Atwood, Mark A. Smith;, Harry Ishiropoulos, Benoit Giasson, John E. Duda, John Q. Trojanowski, and Virginia M.-Y. Lee (26 January 2001) Science291 (5504), 595c.
[DOI: 10.1126/science.291.5504.595C] |Full Text »
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Phosphorylated alpha -Synuclein Is Ubiquitinated in alpha -Synucleinopathy Lesions.
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J. Biol. Chem.
277, 49071-49076
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Parkin Accumulation in Aggresomes Due to Proteasome Impairment.
E. Junn, S. S. Lee, U. T. Suhr, and M. M. Mouradian (2002)
J. Biol. Chem.
277, 47870-47877
|Abstract »|Full Text »|PDF »
Sharing signals: connecting lung epithelial cells with gap junction channels.
Evidence for Early Cytotoxic Aggregates in Transgenic Mice for Human Transthyretin Leu55Pro.
M. M. Sousa, R. Fernandes, J. A. Palha, A. Taboada, P. Vieira, and M. J. Saraiva (2002)
Am. J. Pathol.
161, 1935-1948
|Abstract »|Full Text »|PDF »
Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays.
S. S. Sarang, T. Yoshida, R. Cadet, A. S. Valeras, R. V. Jensen, and S. R. Gullans (2002)
Physiol Genomics
11, 45-52
|Abstract »|Full Text »|PDF »
Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration.
L. Y. Marmorstein, F. L. Munier, Y. Arsenijevic, D. F. Schorderet, P. J. McLaughlin, D. Chung, E. Traboulsi, and A. D. Marmorstein (2002)
PNAS
99, 13067-13072
|Abstract »|Full Text »|PDF »
An In Vitro Model of Parkinson's Disease: Linking Mitochondrial Impairment to Altered alpha -Synuclein Metabolism and Oxidative Damage.
T. B. Sherer, R. Betarbet, A. K. Stout, S. Lund, M. Baptista, A. V. Panov, M. R. Cookson, and J. T. Greenamyre (2002)
J. Neurosci.
22, 7006-7015
|Abstract »|Full Text »|PDF »
Environment, Mitochondria, and Parkinson's Disease.
T. B. Sherer, R. Betarbet, and J. T. Greenamyre (2002)
Neuroscientist
8, 192-197
|Abstract »|PDF »
Tau and {alpha}-Synuclein Pathology in Amygdala of Parkinsonism-Dementia Complex Patients of Guam.
M. S. Forman, M. L. Schmidt, S. Kasturi, D. P. Perl, V. M.-Y. Lee, and J. Q. Trojanowski (2002)
Am. J. Pathol.
160, 1725-1731
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Peroxynitrite-induced Nitration of Tyrosine Hydroxylase. IDENTIFICATION OF TYROSINES 423, 428, AND 432 AS SITES OF MODIFICATION BY MATRIX-ASSISTED LASER DESORPTION IONIZATION TIME-OF-FLIGHT MASS SPECTROMETRY AND TYROSINE-SCANNING MUTAGENESIS.
D. M. Kuhn, M. Sadidi, X. Liu, C. Kreipke, T. Geddes, C. Borges, and J. T. Watson (2002)
J. Biol. Chem.
277, 14336-14342
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Parkinson-Like Neurodegeneration Induced by Targeted Overexpression of alpha -Synuclein in the Nigrostriatal System.
D. Kirik, C. Rosenblad, C. Burger, C. Lundberg, T. E. Johansen, N. Muzyczka, R. J. Mandel, and A. Bjorklund (2002)
J. Neurosci.
22, 2780-2791
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alpha -Synuclein Protects against Oxidative Stress via Inactivation of the c-Jun N-terminal Kinase Stress-signaling Pathway in Neuronal Cells.
M. Hashimoto, L. J. Hsu, E. Rockenstein, T. Takenouchi, M. Mallory, and E. Masliah (2002)
J. Biol. Chem.
277, 11465-11472
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Formation and Removal of alpha -Synuclein Aggregates in Cells Exposed to Mitochondrial Inhibitors.
H.-J. Lee, S. Y. Shin, C. Choi, Y. H. Lee, and S.-J. Lee (2002)
J. Biol. Chem.
277, 5411-5417
|Abstract »|Full Text »|PDF »
Book Review: Iron and Parkinson's Disease.
B. Wolozin and N. Golts (2002)
Neuroscientist
8, 22-32
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Membrane-bound alpha -Synuclein Has a High Aggregation Propensity and the Ability to Seed the Aggregation of the Cytosolic Form.
H.-J. Lee, C. Choi, and S.-J. Lee (2002)
J. Biol. Chem.
277, 671-678
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Selective Insolubility of {alpha}-Synuclein in Human Lewy Body Diseases Is Recapitulated in a Transgenic Mouse Model.
P. J. Kahle, M. Neumann, L. Ozmen, V. Muller, S. Odoy, N. Okamoto, H. Jacobsen, T. Iwatsubo, J. Q. Trojanowski, H. Takahashi, et al. (2001)
Am. J. Pathol.
159, 2215-2225
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Nitration and Inactivation of Tyrosine Hydroxylase by Peroxynitrite.
B. Blanchard-Fillion, J. M. Souza, T. Friel, G. C. T. Jiang, K. Vrana, V. Sharov, L. Barron, C. Schoneich, C. Quijano, B. Alvarez, et al. (2001)
J. Biol. Chem.
276, 46017-46023
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Exposure to Long Chain Polyunsaturated Fatty Acids Triggers Rapid Multimerization of Synucleins.
R. J. Perrin, W. S. Woods, D. F. Clayton, and J. M. George (2001)
J. Biol. Chem.
276, 41958-41962
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In Vivo Retinal Gene Expression in Early Diabetes.
A. M. Joussen, S. Huang, V. Poulaki, K. Camphausen, W.-D. Beecken, B. Kirchhof, and A. P. Adamis (2001)
Invest. Ophthalmol. Vis. Sci.
42, 3047-3057
|Abstract »|Full Text »|PDF »
The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse.
G. P. Lim, T. Chu, F. Yang, W. Beech, S. A. Frautschy, and G. M. Cole (2001)
J. Neurosci.
21, 8370-8377
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Induction of {alpha}-Synuclein Aggregation by Intracellular Nitrative Insult.
E. Paxinou, Q. Chen, M. Weisse, B. I. Giasson, E. H. Norris, S. M. Rueter, J. Q. Trojanowski, V. M.-Y. Lee, and H. Ischiropoulos (2001)
J. Neurosci.
21, 8053-8061
|Abstract »|Full Text »|PDF »
The Hunt for a Cure for Parkinson's Disease.
J. K. Andersen, J. Kumar, B. Srinivas, D. Kaur, M. Hsu, and S. Rajagopalan (2001)
Sci. Aging Knowl. Environ.
2001, re1-1
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-Synuclein Nitration in Synucleinopathy Lesions
-synuclein proteins form brain lesions that are
hallmarks of neurodegenerative synucleinopathies, and oxidative stress
has been implicated in the pathogenesis of some of these disorders.
Using antibodies to specific nitrated tyrosine residues in
