Oxidative post-translational modifications of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease.
Structural and functional alterations of alpha-synuclein is a presumed culprit in the demise of dopaminergic neurons in Parkinson's disease (PD). Alpha-synuclein mutations are found in familial but not in sporadic PD, raising the hypothesis that effects similar to those of familial PD-linked alpha-synuclein mutations may be achieved by oxidative post-translational modifications. Here, we show that wild-type alpha-synuclein is a selective target for nitration following peroxynitrite exposure of stably transfected HEK293 cells. Nitration of alpha-synuclein also occurs in the mouse striatum and ventral midbrain following administration of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Conversely, beta-synuclein and synaptophysin were not nitrated in MPTP-intoxicated mice. Our data demonstrate that alpha-synuclein is a target for tyrosine nitration, which, by disrupting its biophysical properties, may be relevant to the putative role of alpha-synuclein in the neurodegeneration associated with MPTP toxicity and with PD.
Przedborski
S
S
Department of Neurology, Columbia University, New York, NY 10032, USA. SP30@Columbia.edu
Chen
Q
Q
Vila
M
M
Giasson
B I
BI
Djaldatti
R
R
Vukosavic
S
S
Souza
J M
JM
Jackson-Lewis
V
V
Lee
V M
VM
Ischiropoulos
H
H
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000494:pharmacology; D011233:Precipitin Tests; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D016708:Synaptophysin / Q000032:analysis / Q000378:metabolism; D051843:Synucleins; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051844:alpha-Synuclein; D051846:beta-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; C497605:Snca protein, mouse; C497608:Sncb protein, mouse; D016708:Synaptophysin; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D030421:Peroxynitrous Acid; D014443:Tyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine