RESEARCH: Oxidative Damage Linked Directly to Neurodegeneration

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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* E. Duda,1* Ian V. J. Murray,1 Qiping Chen,3

José M. Souza,3 I. Hurtig,2 Harry Ischiropoulos,3 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.

To whom correspondence should be addressed E-mail:

vmylee@....

ABSTRACT:

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.