title: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Olga V
authors.initials: OV
authors.lastname: Savinova
authors.forename: Joseph
authors.initials: J
authors.lastname: Barter
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.forename: Robert W
authors.initials: RW
authors.lastname: Nickells
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John