Oxtoattve injury in the pathogenesis of LHON

J. Guy

Research output: Contribution to journalArticlepeer-review


EUCpQS£ - To investigate our hypothesis that reactive oxygen species (ROS) play a role in the pathogenesis of Lebers Hereditary Optic Neuropathy (LHON). Background - While point mutations of mitochondrial DNA (mlDNA) at nucleotide positions 3460,4160,11,778, or 14,484 result in LHOH, the pathophysiologic processes that contribute to optic nerve head edema are unclear. Superoxide and nitric oxide arc ROS that form peroxynitrite, another highly reactive ROS. Iroxynitrite nitrates tyrosine forming nitrotyrosine. Manganese Superoxide dismutase (MnSOD) is a mitochondria! enzymes that dismutes Superoxide, thus making superoxide unavailable for reaction with nitric oxide. Methods - The optic nerves of a patient with a mutations at positions 14,484 and 4160 of mtDNA and age matched autopsy eyes were fixed in glutaraldehyde (OD) or formalin (OS). Specimens were immunolabeled with antibodies against (a) nitrotyrosine or (b) MnSOD followed by secondary antibodies conjugated to 5 nm colloidal gold, then silver enhanced. Controls were incubated in the secondary antibody only. Results - Nitrotyrosine immunogold heavily labeled nerve fiber bundles of the atrophie left optic nerve of the LHON patient The right optic nerve of the LHON patient that was fixed in glutaraldehyde showed no immunostaining. Minimal nitrotyrosine immunostaining of nerve fiber bundles was seen in the normal age matched optic nerve. Control specimens with the primary antibody omitted from the immunostaining protocol showed noimraunostaiiung. Low levels of MnSOD immunoreactivity were similar in both LHON and normal optic nerves. Concluons - (1) Peroxynitrite mediated nitration of tyrosine in optic nerve fibers suggests ROS may contribute to the pathogenesis of LHON. (2) Compensatory increases in MnSOD that would reduce levels of superoxide available for reaction with nitric oxide were not seen in LHON. (,3) Our results support a role for future studies to demonstrate a beneficial therapeutic effect of ROS scavengers on the visual morbidity of LHON.

Original languageEnglish (US)
Pages (from-to)S382
JournalInvestigative Ophthalmology and Visual Science
Issue number4
StatePublished - Dec 1 1997
Externally publishedYes

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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