Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies.
Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated alpha-synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that alpha-synuclein is nitrated in pathological lesions. The widespread presence of nitrated alpha-synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.
Duda
J E
JE
Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, USA.
Giasson
B I
BI
Chen
Q
Q
Gur
T L
TL
Hurtig
H I
HI
Stern
M B
MB
Gollomp
S M
SM
Ischiropoulos
H
H
Lee
V M
VM
Trojanowski
J Q
JQ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism*; D016631:Lewy Bodies / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D051843:Synucleins; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D051844:alpha-Synuclein
D000906:Antibodies; D009419:Nerve Tissue Proteins; D009566:Nitrates; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C002744:3-nitrotyrosine; D014443:Tyrosine