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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Tahzib, NG; Ransom, NL; Reitsamer, HA; McKinnon, SJ

Published Date

  • February 2004

Published In

Volume / Issue

  • 62 / 6

Start / End Page

  • 491 - 495

PubMed ID

  • 15036563

Pubmed Central ID

  • 15036563

Electronic International Standard Serial Number (EISSN)

  • 1873-2747

International Standard Serial Number (ISSN)

  • 0361-9230

Digital Object Identifier (DOI)

  • 10.1016/s0361-9230(03)00083-2

Language

  • eng