Susceptibility to Neurodegeneration in a Glaucoma Is Modified by Bax Gene Dosage

Abstract

In glaucoma, harmful intraocular pressure often contributes to retinal ganglion cell death. It is not clear, however, if intraocular pressure directly insults the retinal ganglion cell axon, the soma, or both. The pathways that mediate pressure-induced retinal ganglion cell death are poorly defined, and no molecules are known to be required. DBA/2J mice deficient in the proapoptotic molecule BCL2-associated X protein (BAX) were used to investigate the roles of BAX-mediated cell death pathways in glaucoma. Both Bax +/− and Bax −/− mice were protected from retinal ganglion cell death. In contrast, axonal degeneration was not prevented in either Bax +/− or Bax −/− mice. While BAX deficiency did not prevent axonal degeneration, it did slow axonal loss. Additionally, we compared the effects of BAX deficiency on the glaucoma to its effects on retinal ganglion cell death due to two insults that are proposed to participate in glaucoma. As in the glaucoma, BAX deficiency protected retinal ganglion cells after axon injury by optic nerve crush. However, it did not protect retinal ganglion cells from N-methyl-D-aspartate (NMDA)-induced excitotoxicity. BAX is required for retinal ganglion cell death in an inherited glaucoma; however, it is not required for retinal ganglion cell axon degeneration. This indicates that distinct somal and axonal degeneration pathways are active in this glaucoma. Finally, our data support a role for optic nerve injury but not for NMDA receptor-mediated excitotoxicity in this glaucoma. These findings indicate a need to understand axon-specific degeneration pathways in glaucoma, and they suggest that distinct somal and axonal degeneration pathways may need to be targeted to save vision.

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

“…Severely (SEV) affected nerves have extensive axon damage throughout the nerve and obvious axon loss. Axon numbers are significantly different between optic nerves of each damage level (39).…”

“…The method of preparing, staining, and analyzing optic nerves for damage has been previously described and validated (5,8,20,27,34,39). In brief, cross-sections of optic nerve are stained with paraphenylenediamine (PPD), which stains all myelin sheaths but darkly stains the axoplasm of injured or dying axons.…”

“…Collectively, the 10.5-and 12-mo data suggest that longer-term IOP elevation and its associated stresses induce damaging processes that overcome the early protective effects of C3. In D2 glaucoma, apoptosis of RGC somas can be uncoupled from axon degeneration, with specific molecules having differential effects on axons and somas (39). There is no evidence that C3 deficiency differentially affects RGC axons and somas; for example, C3-deficient eyes with severe axon loss also have severe soma loss (Fig.…”

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

“…Studies have also indicated axonopathy as an early feature in neurodegenerative diseases associated with excitotoxicity [13-16]. It is unclear whether the nerve degeneration associated with excitotoxicity is due to primary insult at the perikaryal level in the grey matter or a primary excitotoxic injury in the white matter.…”

Deficiency in Bim, Bid and Bbc3 (Puma) do not prevent axonal injury induced death

“…1 In fact BAX activation appears to require at least one of these pro-apoptotic chaperones during development and after many apoptotic insults. 2 Retinal ganglion cells (RGCs) die by a BAX-dependent mechanism in development and after axonal injury, 3 a key insult in many neurodegenerations. During development BAX-dependent death of RGCs requires BBC3 (Harder and Libby 4 and Supplementary Figure 1A); however, the molecules controlling BAX activation after axonal injury are unknown.…”