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Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice
Masato Koike1, Masahiro Shibata, Yoshiyuki Ohsawa
1Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, 565-0871, Suita, Osaka, Japan.
Abstract:
To understand the mechanisms of retinal atrophy in cathepsin D-deficient mice, the postnatal development of their retinae was analyzed. TUNEL-positive cells appeared abundantly in the outer nuclear layer (ONL) and slightly in the inner nuclear layer (INL). Nitric oxide synthase (NOS) was induced in microglial cells which invaded retinal layers and phagocytosed dead cell debris, while NOS inhibitors prevented cell death in the INL but not in the ONL. Caspases 9 and 3 were activated only in the ONL after P15. Moreover, no atrophic change was detected in the retina of mice deficient in cathepsin B or L. These results suggest that cathepsin D is essential for the metabolic maintenance of retinal photoreceptor cells and that its deficiency induces apoptosis of the cells, while the loss of INL neurons is mediated by NO from microglial cells.
Insights
Cathepsin D deficiency causes retinal atrophy by inducing photoreceptor cell apoptosis and inner nuclear layer neuron loss via nitric oxide. This highlights cathepsin D's crucial role in retinal health.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Retinal atrophy mechanisms are not fully understood.
- Cathepsin D's role in retinal maintenance is unclear.
Purpose of the Study:
- To investigate retinal atrophy mechanisms in cathepsin D-deficient mice.
- To analyze the role of cathepsin D in postnatal retinal development.
Main Methods:
- Postnatal retinal development analysis in cathepsin D-deficient mice.
- TUNEL staining to detect apoptosis.
- Nitric oxide synthase (NOS) and caspase activation assays.
Main Results:
- Abundant apoptosis in the outer nuclear layer (ONL) and inner nuclear layer (INL) of deficient mice.
- NOS induction in microglia; NOS inhibitors reduced INL cell death but not ONL.
- Caspase 9 and 3 activation observed in the ONL after postnatal day 15.
Conclusions:
- Cathepsin D is essential for metabolic maintenance of retinal photoreceptor cells.
- Cathepsin D deficiency induces photoreceptor apoptosis.
- Inner nuclear layer neuron loss is mediated by microglial nitric oxide.
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