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Light-induced retinal damage in mice carrying a mutated SOD I gene
T W Mittag1, A U Bayer, M M La VAIL
1Ophthalmology, Mount Sinai School of Medicine, Box 1183, New York, NY, 10029-6574, USA.
Abstract:
Transgenic mice expressing mutated mouse Cu/Zn superoxide dismutase (SOD I), corresponding to a mutation associated with familial amyotrophic lateral sclerosis, develop a fatal motorneuron degeneration that resembles the human disease. The biochemical properties of some mutant SOD I enzymes indicate that a gain of catalytic functions, (such as increased peroxidase activity) may be the pathologic factor(s). However, at the present time there is little in vivo evidence that a mutation-induced change in the catalytic activity of SOD I is directly involved in neuronal cell death or that vulnerability to cell death is related to the level of functional/metabolic activity of cells carrying mutated SOD I. In pigmented mice carrying the G86R mutation of mouse SOD I, exposure to constant bright light for 20 days caused a diminution of electroretinographic activity and specific degeneration of photoreceptor cells, while no pathological effects were seen in transgenic littermates not exposed to bright light or in light exposed non-transgenic littermates. These findings are the first to indicate that one mechanism for neuronal cell death by mutated SOD I is use-dependent and/or related to metabolic activity, and therefore may be due to a gain in function of catalytic activities involving superoxide/hydrogen peroxide. The light-exposure pathology in this transgenic mouse model indicates an essential role for SOD I in the protection of photoreceptors from light-damage.
Insights
Mutated copper/zinc superoxide dismutase (SOD I) causes motor neuron degeneration. In mice, this mutation leads to photoreceptor cell death when exposed to bright light, suggesting a use-dependent gain of function.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in copper/zinc superoxide dismutase (SOD I).
- Mutant SOD I may cause disease through a gain of catalytic function, but in vivo evidence is limited.
- The relationship between cell metabolic activity and vulnerability to mutant SOD I toxicity is unclear.
Purpose of the Study:
- To investigate the in vivo role of mutated SOD I in neuronal cell death.
- To determine if a gain of catalytic function is responsible for SOD I-induced neurodegeneration.
- To explore the link between cellular activity and susceptibility to mutant SOD I.
Main Methods:
- Transgenic mice expressing a familial ALS-associated G86R mutation in mouse SOD I were used.
- Mice were exposed to constant bright light for 20 days.
- Electroretinography and histological examination of photoreceptor cells were performed.
Main Results:
- Light-exposed transgenic mice showed reduced electroretinographic activity and photoreceptor degeneration.
- Non-transgenic littermates and unexposed transgenic littermates showed no pathology.
- This indicates a use-dependent mechanism for neuronal cell death involving mutated SOD I.
Conclusions:
- Mutated SOD I contributes to neuronal cell death through a use-dependent or metabolic activity-related mechanism.
- A gain in catalytic function involving superoxide/hydrogen peroxide is implicated in the pathology.
- SOD I plays a crucial role in protecting photoreceptor cells from light-induced damage.