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Optic neuropathy induced by reductions in mitochondrial superoxide dismutase
Xiaoping Qi1, Alfred S Lewin, William W Hauswirth
1Department of Ophthalmology, Center for Vision Science, University of Florida, College of Medicine, Gainesville, Florida32610-0284, USA.
Investigative Ophthalmology & Visual Science
|February 26, 2003
Summary
Reactive oxygen species (ROS) contribute to Leber hereditary optic neuropathy (LHON). This study created an animal model by reducing antioxidant defenses, successfully mimicking LHON optic nerve damage.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Leber hereditary optic neuropathy (LHON) is linked to mitochondrial complex I gene mutations.
- Reactive oxygen species (ROS) are implicated in LHON pathogenesis.
- A lack of animal models with optic neuropathy despite reduced antioxidant defenses prompted this investigation.
Purpose of the Study:
- To develop an animal model for studying oxidative injury in the optic nerve.
- To investigate the role of ROS in LHON by increasing mitochondrial ROS levels.
Main Methods:
- Hammerhead ribozymes were designed to degrade SOD2 mRNA, decreasing mitochondrial antioxidant defenses.
- A recombinant adeno-associated virus (rAAV) vector delivered the ribozyme to cells and mice.
- Effects on cellular ROS, apoptosis, optic nerve axons, and retinal ganglion cells were evaluated.
Main Results:
- The rAAV-ribozyme significantly reduced SOD2 mRNA and protein, increased cellular ROS, and induced apoptosis.
- Mice treated with the rAAV-ribozyme showed optic nerve axon and myelin loss, and retinal ganglion cell damage.
- This induced optic neuropathy closely resembled human LHON histopathology.
Conclusions:
- The developed animal model provides strong evidence for ROS's key role in LHON pathogenesis.
- Targeting ROS may offer therapeutic strategies for LHON.
