Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat model of glaucoma.
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.
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- X-Linked Inhibitor of Apoptosis Protein
- Rats, Inbred BN
- Rats
- Proteins
- Ocular Hypertension
- Neurology & Neurosurgery
- Microfilament Proteins
- Hydrolysis
- Glaucoma
- Enzyme Inhibitors
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- X-Linked Inhibitor of Apoptosis Protein
- Rats, Inbred BN
- Rats
- Proteins
- Ocular Hypertension
- Neurology & Neurosurgery
- Microfilament Proteins
- Hydrolysis
- Glaucoma
- Enzyme Inhibitors