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.

References: 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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References

Paper Citations

  1. . Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000 Nov 3;290(5493):985-9. PubMed.
  2. . A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol. 2000 Nov;48(5):730-6. PubMed.

Further Reading

Papers

  1. . Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000 Nov 3;290(5493):985-9. PubMed.
  2. . A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol. 2000 Nov;48(5):730-6. PubMed.

Primary Papers

  1. . Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000 Nov 3;290(5493):985-9. PubMed.
  2. . A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol. 2000 Nov;48(5):730-6. PubMed.