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Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat model of glaucoma
N G Tahzib1, N L Ransom, H A Reitsamer
1Department of Ophthalmology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 6230, San Antonio, TX 78229-3900, USA.
Purpose:
alpha-Fodrin is a neuronal cytoskeletal protein and a known caspase-3 target. We sought to determine whether caspase-3 cleaves alpha-fodrin in COH rat retinas and whether this process is reduced by adeno-associated virus (AAV)-induced retinal ganglion cell expression of baculovirus inhibitory repeat-containing 4 (BIRC4), a potent caspase-3 inhibitor.
Methods:
Ocular hypertension was induced unilaterally in five rat eyes by limbal injection of hypertonic saline. In a similar experiment, ocular hypertension was induced in four eyes pre-treated with an intravitreal injection of AAV-BIRC4 to assess alpha-fodrin cleavage. Western immunoblotting was performed on all retinas.
Results:
Caspase-3 cleavage of alpha-fodrin yields a specific 120kDa protein fragment. COH retina immunoblots indicated significantly more caspase-3 cleavage of alpha-fodrin than controls (P < 0.01, paired t-test). Inhibition of retinal caspase-3 activity with BIRC4 reduced caspase-3-mediated alpha-fodrin cleavage compared to controls.
Conclusions:
This confirms our previous finding of caspase-3 cleavage of alpha-fodrin in COH retinas and parallels pathology seen in Alzheimer's disease, in which neurons undergo chronic caspase activation, slow build-up of cleavage products, and delayed apoptosis. If caspase activation in glaucoma leads to protracted rather than rapid retinal ganglion cell apoptosis, a much longer therapeutic window exists for apoptosis inhibition with caspase inhibitors such as BIRC4.
Insights
Caspase-3 cleaves alpha-fodrin in rat retinas, a process reduced by baculovirus inhibitory repeat-containing 4 (BIRC4). This finding suggests a potential therapeutic window for inhibiting apoptosis in glaucoma.
Area of Science:
- Neuroscience
- Molecular Biology
- Ophthalmology
Background:
- Alpha-fodrin is a neuronal cytoskeletal protein.
- Alpha-fodrin is a known target of caspase-3.
- Caspase-3 activation is implicated in neuronal apoptosis.
Purpose of the Study:
- To determine if caspase-3 cleaves alpha-fodrin in ocular hypertensive rat retinas.
- To investigate if adeno-associated virus (AAV)-mediated expression of baculovirus inhibitory repeat-containing 4 (BIRC4) reduces alpha-fodrin cleavage in these retinas.
Main Methods:
- Ocular hypertension was induced in rat eyes via limbal injection of hypertonic saline.
- Some eyes were pre-treated with intravitreal AAV-BIRC4 to inhibit caspase-3.
- Western immunoblotting was used to analyze retinal samples for alpha-fodrin cleavage.
Main Results:
- Caspase-3 cleavage of alpha-fodrin produces a distinct 120kDa fragment.
- Significantly increased alpha-fodrin cleavage was observed in ocular hypertensive retinas compared to controls.
- BIRC4 treatment significantly reduced caspase-3-mediated alpha-fodrin cleavage.
Conclusions:
- Confirms caspase-3 mediated alpha-fodrin cleavage in ocular hypertensive rat retinas.
- This cleavage process mirrors neuronal pathology in Alzheimer's disease.
- Suggests a potential therapeutic window for caspase inhibitors like BIRC4 in treating glaucoma by inhibiting delayed retinal ganglion cell apoptosis.
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