Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.
Aggregated alpha-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 alpha-synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha-synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha-synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.
Giasson
B I
BI
Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Duda
J E
JE
Murray
I V
IV
Chen
Q
Q
Souza
J M
JM
Hurtig
H I
HI
Ischiropoulos
H
H
Trojanowski
J Q
JQ
Lee
V M
VM
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000737:chemistry; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D016253:Microscopy, Immunoelectron; D019578:Multiple System Atrophy / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051843:Synucleins; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D051844:alpha-Synuclein
D000911:Antibodies, Monoclonal; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C002744:3-nitrotyrosine; D014443:Tyrosine