Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat model of glaucoma

Purpose: α-Fodrin is a neuronal cytoskeletal protein and a known caspase-3 target. We sought to determine whether caspase-3 cleaves α-fodrin in COH rat retinas and whether this process is reduced by adeno-associated virus (AAV)-induced retinal ganglion cell expression of baculovirus inhibitory repea...

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Published in:	Brain research bulletin Vol. 62; no. 6; pp. 491 - 495
Main Authors:	Tahzib, N.G., Ransom, N.L., Reitsamer, H.A., McKinnon, S.J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 15-02-2004
Subjects:	Animals Apoptosis BIRC4 Carrier Proteins - metabolism Caspase 3 Caspase Inhibitors Caspases Caspases - metabolism Chronic Disease Disease Models, Animal Enzyme Inhibitors - pharmacology Glaucoma Glaucoma - enzymology Glaucoma - metabolism Hydrolysis Microfilament Proteins - metabolism Neuroprotection Ocular Hypertension - enzymology Ocular Hypertension - metabolism Proteins - pharmacology Rats Rats, Inbred BN Retinal ganglion cell X-Linked Inhibitor of Apoptosis Protein Glaucoma BIRC4 Neuroprotection Caspases Apoptosis Retinal ganglion cell
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Summary:	Purpose: α-Fodrin is a neuronal cytoskeletal protein and a known caspase-3 target. We sought to determine whether caspase-3 cleaves α-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 α-fodrin cleavage. Western immunoblotting was performed on all retinas. Results: Caspase-3 cleavage of α-fodrin yields a specific 120 kDa protein fragment. COH retina immunoblots indicated significantly more caspase-3 cleavage of α-fodrin than controls ( P<0.01, paired t-test). Inhibition of retinal caspase-3 activity with BIRC4 reduced caspase-3-mediated α-fodrin cleavage compared to controls. Conclusion: This confirms our previous finding of caspase-3 cleavage of α-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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0361-9230 1873-2747
DOI:	10.1016/S0361-9230(03)00083-2