Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death.

Shreyasi Choudhury,Yang Liu,Iok-Hou Pang,Abbot F Clark

doi:10.1186/s13024-015-0039-2

Abstract

BackgroundAxonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision. Caspases have been implicated in RGC pathogenesis. However, the role of caspase-7, a functionally unique caspase, in ON injury and RGC apoptosis has not been reported previously. The purpose of this study is to evaluate the role of caspase-7 in ON injury-induced RGC apoptosis.ResultsC57BL/6 (wildtype, WT) and caspase-7 knockout (Casp7−/−) mice were used. We show that ON crush activated caspase-7 and calpain-1, an upstream activator of caspase-7, in mouse RGCs, as well as hydrolysis of kinectin and co-chaperone P23, specific substrates of caspase-7. ON crush caused a progressive loss of RGCs to 28 days after injury. Knockout of caspase-7 partially and significantly protected against the ON injury-induced RGC loss; RGC density at 28 days post ON crush in Casp7−/− mice was approximately twice of that in WT ON injured retinas. Consistent with changes in RGC counts, spectral-domain optical coherence tomography analysis revealed that ON crush significantly reduced the in vivo thickness of the ganglion cell complex layer (including ganglion cell layer, nerve fiber layer, and inner plexiform layer) in the retina. The ON crush-induced thinning of retinal layer was significantly ameliorated in Casp7−/− mice when compared to WT mice. Moreover, electroretinography analysis demonstrated a decline in the positive component of scotopic threshold response amplitude in ON crushed eyes of the WT mice, whereas this RGC functional response was significantly higher in Casp7−/− mice at 28 days post injury.ConclusionAltogether, our findings indicate that caspase-7 plays a critical role in ON injury-induced RGC death, and inhibition of caspase-7 activity may be a novel therapeutic strategy for glaucoma and other neurodegenerative diseases of the retina.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0039-2) contains supplementary material, which is available to authorized users.

Highlights

Axonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision
Activation of specific caspases occurs in retinas of animal models of ON injury, glaucoma, and RGC degeneration: (a) ON crush activates caspase-2 [5]; (b) ON axotomy activates caspases-3, −6, −8, and −9 in RGCs [6,7,8,9,10,11]; (c) higher levels of active caspases-3, −8, and −9 were shown in the rat retina subjected to chronic ocular hypertension [12,13,14,15,16,17]; (d) retinal ischemia/reperfusion activates both caspases-2 and −3 [18, 19] with a reported reduction in caspase-7 expression [19]; and (e) intravitreal injection of kainate cleaved caspase-3 with an increase in effector caspase activity [20]
Protection of Casp7 knockout against ON crush-induced RGC loss To assess if caspase-7 activation plays a critical role in ON injury-induced RGC apoptosis, we evaluated the effects of ON crush in Casp7−/− mice compared to wild type (WT) animals

Summary

Introduction

Axonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision. Knockout of caspase-7 partially and significantly protected against the ON injury-induced RGC loss; RGC density at 28 days post ON crush in Casp7−/− mice was approximately twice of that in WT ON injured retinas. Activation of specific caspases occurs in retinas of animal models of ON injury, glaucoma, and RGC degeneration: (a) ON crush activates caspase-2 [5]; (b) ON axotomy activates caspases-3, −6, −8, and −9 in RGCs [6,7,8,9,10,11]; (c) higher levels of active caspases-3, −8, and −9 were shown in the rat retina subjected to chronic ocular hypertension [12,13,14,15,16,17]; (d) retinal ischemia/reperfusion activates both caspases-2 and −3 [18, 19] with a reported reduction in caspase-7 expression [19]; and (e) intravitreal injection of kainate cleaved caspase-3 with an increase in effector caspase activity [20]. Other than caspase-2 [5, 21], inhibition or down-regulation of other initiator caspases or caspase-3 only provides partial protection against injury-induced RGC death [7,8,9, 12, 16]

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