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

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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. Glaucoma is a group of diseases whose unifying characteristic is death of nerve cells (retinal ganglion cells) that connect the eye to the brain. Glaucoma is often associated with a harmfully high pressure inside the eye (intraocular pressure) contributing to nerve cell death. Various treatments are used to lower eye pressure, but currently no commonly used treatments directly protect the nerve cells. DBA/2J mice develop elevated eye pressure with age, and this pressure kills retinal nerve cells. The authors use this mouse model to investigate how these nerve cells die in glaucoma. They show that there are distinct degeneration pathways activated in different parts of the retinal nerve cells. They found that the biochemical pathway in the nerve cell body, which resides in the retina, requires a molecule called BAX (BCL2-associated X protein). In contrast, pathways in the part of the cell (axon) that connects the cell body to the brain do not require BAX. Because degeneration pathways in the cell body and of the axon also may be molecularly different in human glaucoma, it will be important to consider them all when designing therapies. Their data also suggest that the BAX gene is a candidate to modulate glaucoma susceptibility.