Glaucoma is a common blinding disease affecting approximately 70 million people worldwide [1
]. Glaucoma is often associated with elevated intraocular pressure (IOP). IOP elevation and glaucoma are typically spontaneous, progressive, idiopathic processes and are most common in the elderly [2
]. Although IOP-lowering treatments slow the development and progression of glaucoma in many patients [3
], it is not always possible to reduce IOP to a “safe” level [5
]. Vision loss in glaucoma is the result of retinal ganglion cell (RGC) death with accompanying optic nerve atrophy, so glaucoma is a neuropathy. IOP elevation is not detected in a significant subset of glaucomas [6
]. Thus, the unifying characteristic of glaucoma is RGC death. While there are several hypotheses as to why elevated IOP kills RGCs, both the precise biochemical cascades that are triggered within RGCs and the nature of the proximal insult(s) that trigger these cascades remain superficially defined [8
]. No treatments that directly protect the neurons are in routine clinical use.
The complex nature of glaucoma makes studies of its pathogenesis difficult [9
]. Consequently, no specific molecules have been shown to be essential for RGC death in glaucoma. Standard glaucoma-relevant models include direct RGC trauma, direct optic nerve trauma, and suddenly induced IOP elevation [10
]. Although these induced models have provided valuable information, the relevance of specific damaging mechanisms may differ significantly between spontaneous and experimentally induced glaucomas. Thus, studies using inherited glaucoma models are also necessary.
Apoptosis is known to contribute to RGC death following experimentally induced insults including axotomy and IOP elevation (e.g.,
]), and there is also some evidence that apoptosis is involved in human glaucoma [21
]. A number of molecules that are known to affect apoptosis are reported to be important regulators of RGC death after various induced insults. These include X-linked inhibitor of apoptosis protein (XIAP) [23
], p38 [26
], several caspases [27
], the B-cell lymphoma/leukemia 2 (BCL2) family of apoptotic regulators [20
], and members of the c-Jun N-terminal kinase (JNK) [35
] and tumor necrosis factor (TNF) [35
] signaling pathways. One of these molecules, BCL2-associated X protein (BAX; a proapoptotic member of the BCL2 family), has a major role in mitochondrial-mediated apoptosis in different neuronal cell types [38
]. In mice, BAX deficiency increases the number of RGCs in the adult retina by 220% by allowing more RGCs to survive during development [39
]. Genetic or induced BAX deficiency is also known to prevent RGC apoptosis after optic nerve crush and axotomy [13
]. Thus, BAX-mediated apoptosis is clearly an important mechanism of stress-induced RGC death. Whether or not this pathway has a role in IOP-induced RGC death in either experimentally induced or inherited glaucomas is not known.
Understanding the pathophysiologic mechanisms of RGC death in glaucoma and the genetic susceptibility factors contributing to this process is important for the development of effective and individualized treatments. Here, we use the genetically uniform DBA/2J mouse model of glaucoma [41
] to assess the importance of mitochondrially mediated apoptosis in an inherited glaucoma. Importantly, we show that in this model of inherited glaucoma there are distinct RGC death and axonal degeneration pathways. The RGC death pathway is BAX dependent and, therefore, apoptotic. The axonal degeneration pathway is BAX independent. Finally, our data suggest that reducing BAX levels in the retina may retard the rate of vision loss in glaucoma.