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7 November 2000. A number of lines of evidence implicate oxidative damage caused by free radicals-particularly reactive oxygen species-as having some role, perhaps even a major or causative one, in the etiology of neurodegenerative diseases.
Writing in Science, Virginia Lee, Benoit Giasson, John Duda, and colleagues at
the University of Pennsylvania, provide a compelling link between oxidative damage
and neurodegeneration in the synucleinopathies. This group of diseases includes
Parkinson's disease and other disorders (e.g., the Lewy body variation of Alzheimer's
disease) that feature Lewy bodies or other abnormal intracellular aggregations
of the protein α-synuclein (α-syn). Using antibodies, the researchers
determined that the α-synuclein in the abnormal aggregations had been modified.
In particular, nitration had taken place at tyrosine residues in α-synuclein,
leaving behind 3-nitrotyrosine (3-NT). How could this nitration have taken place?
The prime candidate would be superoxygen, a free radical that reacts with nitric
oxide to generate peroxynitrite. In the presence of a catalysts (e.g., CO[2],
redox metals, metalloproteins), peroxynitrite forms nitrating agents that can
generate 3-NT.
Such evidence underscores the possibility that future therapies for neurodegenerative
diseases may involve antioxidants to combat the effects of free radicals. This
possibility is also supported by a report in this month's Annals of Neurology,
describing a mutation in the mitochondrial genome that can lead to Parkinson's
disease. Mitochondria are of special interest in neurodegenerative disease because
they produce large numbers of free radicals as a byproduct of producing ATP,
the molecule that powers most chemical reactions in cells. Under normal conditions,
these free radicals are neutralized; under disease conditions, it is hypothesized,
free radicals overwhelm defense mechanisms and damage proteins, lipids, nucleic
acids and other cellular components. Ironically, the mitochondria are themselves
especially vulnerable to oxidative damage.
Researchers at Columbia-Presbyterian Medical Center, led by Dominic Thyagarajan,
determined that a family with clear maternal inheritance of Parkinson's disease
had a mutation of a mitochondrial gene (the 12S rRNA gene). "It has been postulated
that Parkinson's disease, and other late-onset neurodegenerative disorders,
may represent an "exaggeration" of normal aging, related to the accumulation
of reactive oxygen species, mitochondrial DNA damage, and impaired respiratory
chain function, in a vicious cycle," said Salvatore DiMauro, one of the authors.
Mutations in the mitochondrial DNA are probably only rarely the cause of Parkinson's
disease, he points out, but the import of these results is that they confirms
that mitochondrial dysfunction is important in the pathogenesis of Parkinson's
disease. This, in turn, also supports the hypothesis that antioxidant agents
might protect neurons in other forms of Parkinson's disease, as well as in Alzheimer's
and other neurodegenerative diseases.-Hakon Heimer.
Reference:Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM.
Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.
Science 2000 Nov 3;290(5493):985-9. Abstract
Thyagarajan D, Bressman S, Bruno C, Przedborski S, Shanske S, Lynch T, Fahn S, DiMauro S. A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol 2000 Nov;48(5):730-6. Abstract
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Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions.
