Oxidative Damage Linked Directly to Neurodegeneration
November 3, 2000; Westport, CT (Reuters Health) -- The presence of nitrated alpha-synuclein in a variety of cells directly links oxidative damage to various neurodegenerative disorders, according to a report in the November 3rd issue of Science. Alpha-synuclein (a-syn), a highly conserved protein in presynaptic terminals, is the major component of Lewy Bodies (LB) and Lewy Neurites (LN) in Parkinson's Disease and other disorders, as well as in glial and neuronal cytoplasmic inclusions (GCIs and NCIs) of various neurodegenerative diseases, the authors explain.
Because of the evidence of nitration -- in the form of 3-Nitro-Tyrosine (3-NT) -- in a-syn lesions, Dr. Benoit I. Giasson, and colleagues from the University of Pennsylvania in Philadelphia, used monoclonal antibodies to determine whether a-syn is nitrated in any of the hallmark lesions of the so-called synucleinopathies.
According to the results, monoclonal antibodies that recognize the nitrated a-syn robustly labeled numerous LBs, LNs, GCIs, NCIs, and LB-like inclusions from dementia with Lewy Bodies, LB variant of Alzheimer's Disease, Parkinson's Disease, multiple system atrophy, and other brains with neurodegenerative disorders. The monoclonal antibodies also labeled the filamentous a-syn structures that form these lesions, the researchers note, and detect nitrated a-syn only in the fraction of brain containing abnormal a-syn.
In contrast, amyloid plaques from Alzheimer brains, neurofibrillary tangles, the lesions of progressive supranuclear palsy and corticobasal degeneration, and the brains of Pick's Disease patients showed no such reaction with the antibodies, the authors report.
"Thus," the authors conclude, "nitrated a-syn is an integral component of the a-syn filaments that form the defining lesions of diverse synucleinopathies." "This is the first time anybody has identified nitration on a specific protein," asserted senior author Dr. Virginia Lee in a news release.
"Our studies provide conclusive evidence of oxidative damage in alpha-synuclein," she added. "Such stress may be a primary event leading to the onset and progression of neurodegenerative synucleinopathies, particularly Parkinson's. This may pave the way for developing therapies to stop or slow the oxidative damage, and thus slow or reverse the progression of these diseases."
Benoit I. Giasson,1* John E. Duda,1* Ian V. J. Murray,1 Qiping Chen,3 José M. Souza,3 Howard I. Hurtig,2 Harry Ischiropoulos,3 John Q. Trojanowski,1 Virginia M. -Y. Lee1 "Oxidative Damage Linked to Neurodegeneration by Selective Alpha-Synuclein Nitration in Synucleinopathy Lesions," Science, Vol. 290, No. 5493, pp. 985-989 (November 3, 2000).
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.
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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.